# PPAR Genomics and Pharmacogenomics:  Implications for Cardiovascular Disease

Authors: Sharon Cresci
Journal: PPAR Research
 (2008)

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## Abstract

The peroxisome proliferator-activated receptors (PPARs) consist of three related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease.  Numerous pharmacologic studies have assessed the effects of specific PPAR agonists in clinical trials and have provided insight into the clinical effects of these genes while genetic studies have demonstrated clinical associations between PPAR polymorphisms and abnormal cardiovascular phenotypes.  With the abundance of data available from these studies as a background, PPAR pharmacogenetics has  become a promising and rapidly advancing field.  This review focuses on summarizing the current state of understanding of PPAR genetics and pharmacogenetics and the important implications for the individualization of therapy for patients with cardiovascular diseases.


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## Body

## 1. Introduction

PPAR-alpha (PPARα), PPAR-beta/delta (PPARβ/δ), and PPAR-gamma (PPARγ) are nuclear hormone receptor transcription
factor proteins encoded by similarly named genes (PPARA; PPARD; PPARG)
[1, 2]. Each of the PPARs has multiple promoters and more than
one isoform, resulting from alternate splicing, alternative transcription start
sites or both [3–5].  The PPARs have distinct, but overlapping,
tissue expression patterns and act to coordinately regulate multiple metabolic
pathways [1, 2].PPARα is highly expressed in the heart, liver, and
skeletal muscles [2].  In these tissues, PPARα is the central regulator of genes involved in
fatty acid metabolism and appears to mediate the balance between cellular fatty
acid and glucose metabolism, particularly at times of metabolic or physiologic
stress, such as myocardial ischemia, hypertrophy, heart failure, and insulin
resistance [6–15]. In addition, PPARα is involved in the energy substrate and
fiber-type switches that occur in skeletal muscle as a result of conditioning [16] and is involved
in the inflammatory response during vascular atherosclerosis [17–19].PPARγ is highly expressed in both white and brown
adipocytes [2, 20, 21]. PPARγ controls
adipocyte lipid storage and release and is an important mediator of insulin sensitivity
[22, 23].
In addition, PPARγ regulates
adipocyte release of adipokines including tumor necrosis factor alpha (TNFα),
angiotensinogen (AGT),
interleukin-6 (IL-6),
and plasminogen activator inhibitor type 1 (PAI-1) [24].PPARβ/δ, also known as
nuclear hormone receptor 1 (NUC 1) or fatty acid-activated receptor (FAAR), is ubiquitously expressed but is expressed
at higher levels in the brain, adipose tissue, and skin [2, 25].
PPARβ/δ is thought to be critically important in adipocyte and skeletal
muscle fatty acid oxidation and is another important mediator of insulin
sensitivity [26–28]. PPARβ/δ appears to also be involved in obesity
[26–28] and in preventing myocardial
hypertrophy via NF-κB
inhibition [29–31].The PPARs are able to bind many
different ligands including metabolic intermediates (fatty acids),
pharmacologic agents (fibrates, thiazolidinediones), and natural herbs (green
tea) [32–36].
In the presence of ligand, PPARs bind to their cognate regulatory
elements as a heterodimer with retinoid X receptor α [37]. Ligand binding causes a conformational change
that results in the recruitment of coactivators and increased transcriptional
activation of target genes [34, 35, 38, 39].There is considerable clinical
association data linking polymorphisms ofPPARA,
PPARD, and PPARG with cardiovascular disease (coronary and carotid atherosclerosis, left
ventricular hypertrophy) and cardiovascular risk factors (incidence of type 2
diabetes mellitus (DM), obesity, insulin resistance, and abnormal lipid
profiles) in populations of diverse ethnicity.
There is less data on PPAR
pharmacogenetics, but the field is rapidly growing and of considerable interest
to many investigators.  PPAR
pharmacogenetics of fibrates (gemfibrozil, fenofibrate, and bezafibrate), thiazolidinediones
or glitazones (troglitazone, pioglitazone, and rosiglitazone), statins, and acarbose have particular relevance to
cardiovascular disease.This review will discuss several significant
PPAR genetic and pharmacogenetic associations that have been observed with
respect to cardiovascular disease (Table1 provides the rs number for each SNP
discussed in this review). Understanding
the current state of PPAR genetics and pharmacogenetics may have important
implications for the future individualization of therapy for patients with cardiovascular
disease.Table 1
SNPrs numberPPARALeu162Valrs1800206Val227Alars1800234IVS7 2498rs4253778IVS7 1343rs4253776PPARGPro12Alars180128225,506 C > Trs202875954,347 C > Trs3856806PPARD−87 T > Crs9658134−4,401 C > Trs2038068−48,444
C > Trs6902123


## 2.PPARA

### 2.1. PPARA Leu162Val Genetic Associations

#### 2.1.1. Dyslipidemias

PPARA Leu162Val is a polymorphism located in the DNA binding region of PPARα that confers differential ligand-mediated
activation of PPARα in vitro [40, 41].
Investigators from several clinical studies have observed that carriers
of the PPARA Val162 allele, compared to PPARA Leu162 homozygotes,
have significantly higher concentrations of serum triglycerides, total
cholesterol, LDL cholesterol, and apolipoprotein (apo) B and apoC-III. However,
there have been exceptions, and not all studies have found an association with
all five serum lipids [41–45].
The larger trial findings, as well as the studies that have negative
findings, will be discussed here.Recently, the association of thePPARA Leu162Val polymorphism with serum lipid levels was investigated in 5799
individuals from the Inter99 cohort, a Danish cohort targeted for identifying
parameters affecting participation in a diet and exercise intervention in the
general population [46].
In this cohort, individuals homozygous for the PPARA Val162
allele, compared to PPARA Leu162 allele carriers, demonstrated a 70% greater
mean fasting serum triglyceride level (2.2 mmol/L (195 mg/dL) versus 1.3 mmol/L
(115 mg/dL), resp.; P = .007) and a greater mean fasting serum
total cholesterol levels (6.2 mmol/L (240 mg/dL) versus 5.5 mmol/L (213 mg/dL),
resp.; P = .01) [45].These findings confirmed previous
observations in 2373 participants of the Framingham Offspring Study.  When the association of thePPARA Leu162Val
polymorphism with variation in lipid levels was investigated in these subjects, PPARA Val162 carriers, compared to PPARA Leu162 homozygotes, had significantly
increased serum concentrations of total cholesterol in men (P = .0012),
LDL cholesterol in men (P = .0004), apoC-III in men (P = .009), and
apoB in men and women (P = .009 and .03, resp.) [44].
These same investigators went on to demonstrate that the association of
the PPARA Leu 162Val polymorphism on plasma triglycerides and apoC-III
concentrations was more complex and depended on the person's regular dietary polyunsaturated
fatty acid intake.  PPARA Val162 allele
carriers that had a low polyunsaturated fatty acid intake (<6% of calories)
had greater serum triglyceride and apoC-III concentrations,compared to PPARA Leu162
homozygotes, whereas PPARA Val162 allele carriers that had a high polyunsaturated
fatty acid intake had lower triglyceride and apoC-III concentrations, compared
to PPARA Leu162 homozygotes [47].Other studies have also investigated
the association of thePPARA Leu162Val polymorphism with serum lipid
response to diets of different fat composition.
Tanaka et al. studied 59 healthy male students fed a single high-fat
meal (60% calories as fat (63% saturated fatty acids, 33% monounsaturated fatty
acids, and 4% polyunsaturated fatty acids); 15% calories as protein; and 25%
calories as carbohydrate) following a 12-hour fast [48]. PPARA Val162 allele carriers had significantly higher fasting
(baseline) total cholesterol, LDL cholesterol, and apoB levels, compared to
Leu162 homozygotes and this variation in serum lipids was maintained after the
high-fat meal [48].
No significant association of the PPARA Leu162Val polymorphism
with serum triglyceride concentrations (either fasting or postprandial) was observed
(apoCIII was not measured) [48].
Paradis et al. investigated the association of the PPARA Leu162Val polymorphism with serum lipid response in ten PPARA Val162 allele
carriers and ten age and body mass index-matched PPARA Leu162 homozygotes
subjected to a high polyunsaturated fat followed by a low polyunsaturated fat diet [49].
At baseline, the PPARA Leu162Val polymorphism was not associated
with variation in serum lipids [49].
After the high polyunsaturated fat diet, PPARA Val162 allele carriers had
a significant decrease in plasma apoA-I levels, total cholesterol, and LDL cholesterol
(small particles), compared to the PPARA Leu162 homozygotes (who demonstrated an
increase in plasma apoA-I levels, total cholesterol, and LDL cholesterol (small
particles): P = .02, P = .07 and P = .08, resp.) [49].In contrast to the aforementioned
studies, when the association of thePPARA Leu162Val polymorphism with
variations in serum lipids was investigated in 3012 healthy middle-aged men in
the second Northwick Park Health Study (NPHS2, Northwick, UK), no association of the PPARA Leu162Val polymorphism with serum lipids at baseline, or in response to therapy,
was found [50].
Although it was a smaller study, the Lopid Coronary Angiography Trial
(LOCAT), a clinical trial of 395 postcoronary bypass men, with an HDL
cholesterol ≤1.1 mmol/L and LDL cholesterol ≤4.5 mmol/L
that investigated the progression of coronary atherosclerosis in
response to lipid lowering therapy with gemfibrozil, [51, 52] also found no association between the PPARA Leu162Val polymorphism and serum lipids either at baseline, or in
response to therapy [50].


#### 2.1.2. Coronary Atherosclerosis

As discussed above, LOCAT found no association of thePPARA Leu162Val
polymorphism with variations in serum lipids [50].
However, this study did observe that carriers of the PPARA Val162
allele showed significantly less progression of atherosclerosis in both gemfibrozil-treated
and untreated groups [50].
No pharmacogenetic (i.e., treatment by genotype) interaction was found [50].


### 2.2. PPARA Leu162Val Pharmacogenetic Associations

#### 2.2.1. Response to Gemfibrozil

The Helsinki Heart Study (Helsinki, Finland) was a primary prevention
trial that demonstrated that randomization to treatment with gemfibrozil
resulted in a 34% reduction in cumulative cardiac events and a 26% reduction in
cardiac mortality [53, 54].
Subgroup analysis demonstrated that overweight men with body mass index
between 27–40 kg/m2 had the largest reduction in cardiac events in
response to gemfibrozil in the Helsinki Heart study [55].
Given that the greatest response to gemfibrozil was observed in this
group, the association between genetic variation in the PPARA Leu162Val
polymorphism and the response to gemfibrozil was investigated in 63 abdominally
obese men in a randomized placebo-controlled trial [56].
After 6 months of treatment, carriers of the PPARA Val162 allele
demonstrated a 50% increase in HDL2 cholesterol compared to PPARA Leu162 allele homozygotes who only had a 5.5% increase (P = .03) [56].
The PPARA Leu162Val was responsible for 7% of the variance of the
change in HDL2 cholesterol and there was a significant
genotype-by-treatment interaction between the PPARA Leu162Val
polymorphism and the increase in HDL2 cholesterol [56].The Veterans Affairs High-Density
Lipoprotein Intervention Trial (VA-HIT) study of patients with known ischemic
heart disease, selected for low levels of HDL cholesterol (mean of 32 mg/dL), demonstrated
that randomization to gemfibrozil therapy resulted in a 22% reduction in relative
risk of coronary events and a 31% reduction in cerebral vascular events [57–59].
In VA-HIT, the subgroup that benefited the most in reduction of
cardiovascular events in response to gemfibrozil were those patients that had DM
or insulin resistance [60, 61]. Given that this group had
demonstrated the greatest response, the association between genetic variation
in the PPARA Leu162Val polymorphism and the response to gemfibrozil was
investigated [62].
VA-HIT patients with DM or insulin resistance treated with gemfibrozil who
were PPARA Leu162 homozygotes had a greater absolute reduction in
cardiovascular events (12.1% reduction compared to treatment with placebo; P =
.06) compared to carriers of the PPARA Val162 allele who had a nonsignificant
reduction (9.9% compared to treatment with placebo; P = .28) [62].
Furthermore, in VA-HIT patients without DM or insulin resistance, carriers
of the Val162 allele had a significant increase in cardiovascular events in
response to gemfibrozil (7% increase compared to
treatment with placebo; P = .01) [62].


#### 2.2.2. Response to Fenofibrate

The Genetics of Lipid Lowering
Drugs and Diet Network  (GOLDN) study
investigated the response to fenofibrate (160 mg) for ≥21 days
in 791 men and women enrolled in The Family Heart Study (FHS, a multicenter, family pedigree study aimed to identify genetic and environmental risk factors of
cardiovascular disease)
[63].
Overall, there was a 37 mg/dL reduction in fasting serum triglyceride
levels after treatment with fenofibrate (the average of two separate
measurements obtained prior to treatment and at the end of treatment were
used).  Although only reported in
abstract form to date, variation in PPARA Leu162Val polymorphism was significantly
associated with fasting triglyceride level response to fenofibrate treatment [64].
Individuals homozygous for the PPARA Val162 allele had a 73 mg/dL
reduction in their fasting triglyceride response to fenofibrate compared to PPARA Leu162Val heterozygotes (46 mg/dL reduction) and PPARA 162Leu homozygotes
(53 mg/dL reduction; P < .0001)
[64].


### 2.3. PPARA Val227Ala Genetic Associations

#### 2.3.1. Dyslipidemias

PPARA Val227Ala is a polymorphism located between the DNA binding and ligand binding
domain of PPARα.  This region is thought to be important in heterodimerization
but in vitro experiments confirming a functional difference in alleles have not
yet been performed [65].
The association of the PPARA Val227Ala polymorphism with serum
lipid levels was investigated in a study of 401 healthy Japanese individuals
presenting to medical clinic for routine health care [65]. After adjustment for age and body mass index, female
carriers of the Val227 allele had significantly lower serum total cholesterol (P =
.046) and triglyceride levels (P = .038) compared to Ala227 homozygotes [65].
Male carriers of the Val227 allele also had lower serum total
cholesterol and triglyceride levels compared to Ala227 homozygotes, but the
differences were not significant (P = .30 and .54, resp.) [65].Recently, the finding of this small
study was confirmed in 2899 Chinese individuals from the 1998 Singapore National
Health Survey (NHS98) [66]. Women PPARA Ala227 allele carriers had
significantly lower serum total cholesterol (P = .047) and triglyceride
levels (P = .048), compared to PPARA Val227 homozygotes, and men
had lower levels that were, again, not significant (P = .65 and .12, resp.) [66].
In addition to these findings, this study also found a significant
interaction between the PPARA Val227Ala polymorphism and serum HDL cholesterol
levels in response to dietary polyunsaturated fatty acid intake in women
suggesting a gene-environment interaction (P-value for interaction = .049)
[66].
Specifically, the authors found that, in women who were PPARA Ala227 allele carriers, increasing dietary polyunsaturated fatty acid intake
resulted in lower serum HDL cholesterol levels.
This result was in contrast to male PPARA Ala227 allele carriers,
who had an increase in serum HDL cholesterol levels, and women who were PPARA Val227 homozygotes, who demonstrated less lowering [66].


### 2.4. PPARA IVS7 2498 G > C  Genetic Associations

#### 2.4.1. Coronary Atherosclerosis

PPARA IVS7 2498 is a polymorphism located in intron 7 of PPARA.  The functional significance of this
polymorphism has remained elusive but significant clinical associations have
been found with this polymorphism.  In
LOCAT, PPARA IVS7 2498 (designated “PPARA intron 7 G/C
polymorphism” in the publication) C allele carriers had a significantly greater
progression of coronary atherosclerosis compared with GG homozygotes [50].
No pharmacogenetic interaction was noted [50].
When the association of PPARA IVS7 2498 polymorphism with
coronary atherosclerosis was investigated in 3,012 healthy middle-aged men in NPHS2, PPARA IVS7 2498 CC homozygotes showed a trend toward greater incidence
of ischemic events (myocardial infarction (MI) or coronary revascularization)
(HR 1.83; 95% CI 0.96–3.51; P = .07) compared to PPARA IVS7 2498 CG
heterozygotes and PPARA IVS7 2498 GG homozygotes
[50].


#### 2.4.2. Left Ventricular Hypertrophy

ThePPARA IVS7 2498 (designated “PPARA intron 7 G/C
polymorphism” in the publication) has also been associated with physiologic
left ventricular hypertrophy in 144 young male British army recruits undergoing
a rigorous ten-week exercise program (mixed upper and lower body strength and
endurance training) [67].
This polymorphism has also been associated with pathologic left
ventricular hypertrophy in 1148 hypertensive men and women enrolled in an
echocardiography substudy of the third monitoring trends and determinants in
cardiovascular disease (MONICA) Augsburg study [67].
In both studies, the PPARA IVS7 2498 C allele was significantly
associated with increased LV
mass index [67].


### 2.5. PPARA IVS7 2498 G > C Pharmacogenetic Associations

#### 2.5.1. Response to Fenofibrate

The Diabetes Atherosclerosis Intervention Study
(DAIS) was designed to investigate if fenofibrate treatment of relatively mild
dyslipidemia in 418 patients with type 2 DM would be associated with less progression
of coronary atherosclerosis after treatment for at least 3 years with
fenofibrate [68].
DAIS found that fenofibrate reduced the
progression of angiographic coronary artery disease [69], the progression of
microalbuminuria (an early marker of diabetic nephropathy, and an independent
risk factor for cardiovascular disease) [70]; and although not
powered to examine clinical events, there were fewer in the fenofibrate group compared to the
placebo group [69].  Given these findings, the association between genetic
variation in the PPARA IVS7 2498 polymorphism (designated “PPARA intron 7 G/C polymorphism” in the publication) and response to fenofibrate in
DAIS was investigated [71].
DAIS subjects were divided into high responders (greater than 30%
reduction, chosen because 30% was the mean reduction in DAIS) and low
responders (less than 30% reduction) in their plasma triglyceride levels and the
prevalence of PPARA IVS7 2498 genotype in the two groups was assessed [71].
Of the 85 high responders (55% of population), there was a significantly
different prevalence of PPARA IVS7 2498 GG homozygotes (84.7%) when
compared to the low responders (68.6%; P < .05) [71].
In stepwise logistic regression analysis, the best independent
predictors of response to fenofibrate treatment were baseline triglyceride
level and PPARA IVS7 2498 genotype (PPARA IVS7 2498 GG versus C
allele carriers response to fenofibrate: OR 3.1; 95% CI 1.28–7.52; P = .012)
[71].


#### 2.5.2. Response to Acarbose

Investigators from the STOP-NIDDM trial were
interested in whetherPPARA polymorphisms would be associated with the conversion to type 2 DM in response
to acarbose in patients with impaired glucose tolerance [72, 73].
They investigated this association with 11 SNPs located from exon 1 to
exon 8 of PPARA and found that in the
acarbose-treated group, PPARA IVS7 2498 (designated “rs4253778” in the publication) CC
homozygotes had a 2.7-fold risk of developing type 2 DM (95% CI 1.14–6.79; P = .03) [74]. PPARA IVS7 1343 (designated “rs4253776” in the publication), a
SNP located1,155 nucleotides upstream of PPARA IVS7 2498 and in moderate
LD with PPARA IVS7 2498 (r2 of 0.565 in this population),
also had an association with the development of type 2 DM [74]. PPARA IVS7 1343 G allele
carriers had a 1.7-fold increased risk of developing type 2 DM (95% CI 1.04–2.88; P = .04) and a significant
treatment by genotype interaction was observed [74].


## 2.1. PPARA Leu162Val Genetic Associations

### 2.1.1. Dyslipidemias

PPARA Leu162Val is a polymorphism located in the DNA binding region of PPARα that confers differential ligand-mediated
activation of PPARα in vitro [40, 41].
Investigators from several clinical studies have observed that carriers
of the PPARA Val162 allele, compared to PPARA Leu162 homozygotes,
have significantly higher concentrations of serum triglycerides, total
cholesterol, LDL cholesterol, and apolipoprotein (apo) B and apoC-III. However,
there have been exceptions, and not all studies have found an association with
all five serum lipids [41–45].
The larger trial findings, as well as the studies that have negative
findings, will be discussed here.Recently, the association of thePPARA Leu162Val polymorphism with serum lipid levels was investigated in 5799
individuals from the Inter99 cohort, a Danish cohort targeted for identifying
parameters affecting participation in a diet and exercise intervention in the
general population [46].
In this cohort, individuals homozygous for the PPARA Val162
allele, compared to PPARA Leu162 allele carriers, demonstrated a 70% greater
mean fasting serum triglyceride level (2.2 mmol/L (195 mg/dL) versus 1.3 mmol/L
(115 mg/dL), resp.; P = .007) and a greater mean fasting serum
total cholesterol levels (6.2 mmol/L (240 mg/dL) versus 5.5 mmol/L (213 mg/dL),
resp.; P = .01) [45].These findings confirmed previous
observations in 2373 participants of the Framingham Offspring Study.  When the association of thePPARA Leu162Val
polymorphism with variation in lipid levels was investigated in these subjects, PPARA Val162 carriers, compared to PPARA Leu162 homozygotes, had significantly
increased serum concentrations of total cholesterol in men (P = .0012),
LDL cholesterol in men (P = .0004), apoC-III in men (P = .009), and
apoB in men and women (P = .009 and .03, resp.) [44].
These same investigators went on to demonstrate that the association of
the PPARA Leu 162Val polymorphism on plasma triglycerides and apoC-III
concentrations was more complex and depended on the person's regular dietary polyunsaturated
fatty acid intake.  PPARA Val162 allele
carriers that had a low polyunsaturated fatty acid intake (<6% of calories)
had greater serum triglyceride and apoC-III concentrations,compared to PPARA Leu162
homozygotes, whereas PPARA Val162 allele carriers that had a high polyunsaturated
fatty acid intake had lower triglyceride and apoC-III concentrations, compared
to PPARA Leu162 homozygotes [47].Other studies have also investigated
the association of thePPARA Leu162Val polymorphism with serum lipid
response to diets of different fat composition.
Tanaka et al. studied 59 healthy male students fed a single high-fat
meal (60% calories as fat (63% saturated fatty acids, 33% monounsaturated fatty
acids, and 4% polyunsaturated fatty acids); 15% calories as protein; and 25%
calories as carbohydrate) following a 12-hour fast [48]. PPARA Val162 allele carriers had significantly higher fasting
(baseline) total cholesterol, LDL cholesterol, and apoB levels, compared to
Leu162 homozygotes and this variation in serum lipids was maintained after the
high-fat meal [48].
No significant association of the PPARA Leu162Val polymorphism
with serum triglyceride concentrations (either fasting or postprandial) was observed
(apoCIII was not measured) [48].
Paradis et al. investigated the association of the PPARA Leu162Val polymorphism with serum lipid response in ten PPARA Val162 allele
carriers and ten age and body mass index-matched PPARA Leu162 homozygotes
subjected to a high polyunsaturated fat followed by a low polyunsaturated fat diet [49].
At baseline, the PPARA Leu162Val polymorphism was not associated
with variation in serum lipids [49].
After the high polyunsaturated fat diet, PPARA Val162 allele carriers had
a significant decrease in plasma apoA-I levels, total cholesterol, and LDL cholesterol
(small particles), compared to the PPARA Leu162 homozygotes (who demonstrated an
increase in plasma apoA-I levels, total cholesterol, and LDL cholesterol (small
particles): P = .02, P = .07 and P = .08, resp.) [49].In contrast to the aforementioned
studies, when the association of thePPARA Leu162Val polymorphism with
variations in serum lipids was investigated in 3012 healthy middle-aged men in
the second Northwick Park Health Study (NPHS2, Northwick, UK), no association of the PPARA Leu162Val polymorphism with serum lipids at baseline, or in response to therapy,
was found [50].
Although it was a smaller study, the Lopid Coronary Angiography Trial
(LOCAT), a clinical trial of 395 postcoronary bypass men, with an HDL
cholesterol ≤1.1 mmol/L and LDL cholesterol ≤4.5 mmol/L
that investigated the progression of coronary atherosclerosis in
response to lipid lowering therapy with gemfibrozil, [51, 52] also found no association between the PPARA Leu162Val polymorphism and serum lipids either at baseline, or in
response to therapy [50].


### 2.1.2. Coronary Atherosclerosis

As discussed above, LOCAT found no association of thePPARA Leu162Val
polymorphism with variations in serum lipids [50].
However, this study did observe that carriers of the PPARA Val162
allele showed significantly less progression of atherosclerosis in both gemfibrozil-treated
and untreated groups [50].
No pharmacogenetic (i.e., treatment by genotype) interaction was found [50].


## 2.1.1. Dyslipidemias

PPARA Leu162Val is a polymorphism located in the DNA binding region of PPARα that confers differential ligand-mediated
activation of PPARα in vitro [40, 41].
Investigators from several clinical studies have observed that carriers
of the PPARA Val162 allele, compared to PPARA Leu162 homozygotes,
have significantly higher concentrations of serum triglycerides, total
cholesterol, LDL cholesterol, and apolipoprotein (apo) B and apoC-III. However,
there have been exceptions, and not all studies have found an association with
all five serum lipids [41–45].
The larger trial findings, as well as the studies that have negative
findings, will be discussed here.Recently, the association of thePPARA Leu162Val polymorphism with serum lipid levels was investigated in 5799
individuals from the Inter99 cohort, a Danish cohort targeted for identifying
parameters affecting participation in a diet and exercise intervention in the
general population [46].
In this cohort, individuals homozygous for the PPARA Val162
allele, compared to PPARA Leu162 allele carriers, demonstrated a 70% greater
mean fasting serum triglyceride level (2.2 mmol/L (195 mg/dL) versus 1.3 mmol/L
(115 mg/dL), resp.; P = .007) and a greater mean fasting serum
total cholesterol levels (6.2 mmol/L (240 mg/dL) versus 5.5 mmol/L (213 mg/dL),
resp.; P = .01) [45].These findings confirmed previous
observations in 2373 participants of the Framingham Offspring Study.  When the association of thePPARA Leu162Val
polymorphism with variation in lipid levels was investigated in these subjects, PPARA Val162 carriers, compared to PPARA Leu162 homozygotes, had significantly
increased serum concentrations of total cholesterol in men (P = .0012),
LDL cholesterol in men (P = .0004), apoC-III in men (P = .009), and
apoB in men and women (P = .009 and .03, resp.) [44].
These same investigators went on to demonstrate that the association of
the PPARA Leu 162Val polymorphism on plasma triglycerides and apoC-III
concentrations was more complex and depended on the person's regular dietary polyunsaturated
fatty acid intake.  PPARA Val162 allele
carriers that had a low polyunsaturated fatty acid intake (<6% of calories)
had greater serum triglyceride and apoC-III concentrations,compared to PPARA Leu162
homozygotes, whereas PPARA Val162 allele carriers that had a high polyunsaturated
fatty acid intake had lower triglyceride and apoC-III concentrations, compared
to PPARA Leu162 homozygotes [47].Other studies have also investigated
the association of thePPARA Leu162Val polymorphism with serum lipid
response to diets of different fat composition.
Tanaka et al. studied 59 healthy male students fed a single high-fat
meal (60% calories as fat (63% saturated fatty acids, 33% monounsaturated fatty
acids, and 4% polyunsaturated fatty acids); 15% calories as protein; and 25%
calories as carbohydrate) following a 12-hour fast [48]. PPARA Val162 allele carriers had significantly higher fasting
(baseline) total cholesterol, LDL cholesterol, and apoB levels, compared to
Leu162 homozygotes and this variation in serum lipids was maintained after the
high-fat meal [48].
No significant association of the PPARA Leu162Val polymorphism
with serum triglyceride concentrations (either fasting or postprandial) was observed
(apoCIII was not measured) [48].
Paradis et al. investigated the association of the PPARA Leu162Val polymorphism with serum lipid response in ten PPARA Val162 allele
carriers and ten age and body mass index-matched PPARA Leu162 homozygotes
subjected to a high polyunsaturated fat followed by a low polyunsaturated fat diet [49].
At baseline, the PPARA Leu162Val polymorphism was not associated
with variation in serum lipids [49].
After the high polyunsaturated fat diet, PPARA Val162 allele carriers had
a significant decrease in plasma apoA-I levels, total cholesterol, and LDL cholesterol
(small particles), compared to the PPARA Leu162 homozygotes (who demonstrated an
increase in plasma apoA-I levels, total cholesterol, and LDL cholesterol (small
particles): P = .02, P = .07 and P = .08, resp.) [49].In contrast to the aforementioned
studies, when the association of thePPARA Leu162Val polymorphism with
variations in serum lipids was investigated in 3012 healthy middle-aged men in
the second Northwick Park Health Study (NPHS2, Northwick, UK), no association of the PPARA Leu162Val polymorphism with serum lipids at baseline, or in response to therapy,
was found [50].
Although it was a smaller study, the Lopid Coronary Angiography Trial
(LOCAT), a clinical trial of 395 postcoronary bypass men, with an HDL
cholesterol ≤1.1 mmol/L and LDL cholesterol ≤4.5 mmol/L
that investigated the progression of coronary atherosclerosis in
response to lipid lowering therapy with gemfibrozil, [51, 52] also found no association between the PPARA Leu162Val polymorphism and serum lipids either at baseline, or in
response to therapy [50].


## 2.1.2. Coronary Atherosclerosis

As discussed above, LOCAT found no association of thePPARA Leu162Val
polymorphism with variations in serum lipids [50].
However, this study did observe that carriers of the PPARA Val162
allele showed significantly less progression of atherosclerosis in both gemfibrozil-treated
and untreated groups [50].
No pharmacogenetic (i.e., treatment by genotype) interaction was found [50].


## 2.2. PPARA Leu162Val Pharmacogenetic Associations

### 2.2.1. Response to Gemfibrozil

The Helsinki Heart Study (Helsinki, Finland) was a primary prevention
trial that demonstrated that randomization to treatment with gemfibrozil
resulted in a 34% reduction in cumulative cardiac events and a 26% reduction in
cardiac mortality [53, 54].
Subgroup analysis demonstrated that overweight men with body mass index
between 27–40 kg/m2 had the largest reduction in cardiac events in
response to gemfibrozil in the Helsinki Heart study [55].
Given that the greatest response to gemfibrozil was observed in this
group, the association between genetic variation in the PPARA Leu162Val
polymorphism and the response to gemfibrozil was investigated in 63 abdominally
obese men in a randomized placebo-controlled trial [56].
After 6 months of treatment, carriers of the PPARA Val162 allele
demonstrated a 50% increase in HDL2 cholesterol compared to PPARA Leu162 allele homozygotes who only had a 5.5% increase (P = .03) [56].
The PPARA Leu162Val was responsible for 7% of the variance of the
change in HDL2 cholesterol and there was a significant
genotype-by-treatment interaction between the PPARA Leu162Val
polymorphism and the increase in HDL2 cholesterol [56].The Veterans Affairs High-Density
Lipoprotein Intervention Trial (VA-HIT) study of patients with known ischemic
heart disease, selected for low levels of HDL cholesterol (mean of 32 mg/dL), demonstrated
that randomization to gemfibrozil therapy resulted in a 22% reduction in relative
risk of coronary events and a 31% reduction in cerebral vascular events [57–59].
In VA-HIT, the subgroup that benefited the most in reduction of
cardiovascular events in response to gemfibrozil were those patients that had DM
or insulin resistance [60, 61]. Given that this group had
demonstrated the greatest response, the association between genetic variation
in the PPARA Leu162Val polymorphism and the response to gemfibrozil was
investigated [62].
VA-HIT patients with DM or insulin resistance treated with gemfibrozil who
were PPARA Leu162 homozygotes had a greater absolute reduction in
cardiovascular events (12.1% reduction compared to treatment with placebo; P =
.06) compared to carriers of the PPARA Val162 allele who had a nonsignificant
reduction (9.9% compared to treatment with placebo; P = .28) [62].
Furthermore, in VA-HIT patients without DM or insulin resistance, carriers
of the Val162 allele had a significant increase in cardiovascular events in
response to gemfibrozil (7% increase compared to
treatment with placebo; P = .01) [62].


### 2.2.2. Response to Fenofibrate

The Genetics of Lipid Lowering
Drugs and Diet Network  (GOLDN) study
investigated the response to fenofibrate (160 mg) for ≥21 days
in 791 men and women enrolled in The Family Heart Study (FHS, a multicenter, family pedigree study aimed to identify genetic and environmental risk factors of
cardiovascular disease)
[63].
Overall, there was a 37 mg/dL reduction in fasting serum triglyceride
levels after treatment with fenofibrate (the average of two separate
measurements obtained prior to treatment and at the end of treatment were
used).  Although only reported in
abstract form to date, variation in PPARA Leu162Val polymorphism was significantly
associated with fasting triglyceride level response to fenofibrate treatment [64].
Individuals homozygous for the PPARA Val162 allele had a 73 mg/dL
reduction in their fasting triglyceride response to fenofibrate compared to PPARA Leu162Val heterozygotes (46 mg/dL reduction) and PPARA 162Leu homozygotes
(53 mg/dL reduction; P < .0001)
[64].


## 2.2.1. Response to Gemfibrozil

The Helsinki Heart Study (Helsinki, Finland) was a primary prevention
trial that demonstrated that randomization to treatment with gemfibrozil
resulted in a 34% reduction in cumulative cardiac events and a 26% reduction in
cardiac mortality [53, 54].
Subgroup analysis demonstrated that overweight men with body mass index
between 27–40 kg/m2 had the largest reduction in cardiac events in
response to gemfibrozil in the Helsinki Heart study [55].
Given that the greatest response to gemfibrozil was observed in this
group, the association between genetic variation in the PPARA Leu162Val
polymorphism and the response to gemfibrozil was investigated in 63 abdominally
obese men in a randomized placebo-controlled trial [56].
After 6 months of treatment, carriers of the PPARA Val162 allele
demonstrated a 50% increase in HDL2 cholesterol compared to PPARA Leu162 allele homozygotes who only had a 5.5% increase (P = .03) [56].
The PPARA Leu162Val was responsible for 7% of the variance of the
change in HDL2 cholesterol and there was a significant
genotype-by-treatment interaction between the PPARA Leu162Val
polymorphism and the increase in HDL2 cholesterol [56].The Veterans Affairs High-Density
Lipoprotein Intervention Trial (VA-HIT) study of patients with known ischemic
heart disease, selected for low levels of HDL cholesterol (mean of 32 mg/dL), demonstrated
that randomization to gemfibrozil therapy resulted in a 22% reduction in relative
risk of coronary events and a 31% reduction in cerebral vascular events [57–59].
In VA-HIT, the subgroup that benefited the most in reduction of
cardiovascular events in response to gemfibrozil were those patients that had DM
or insulin resistance [60, 61]. Given that this group had
demonstrated the greatest response, the association between genetic variation
in the PPARA Leu162Val polymorphism and the response to gemfibrozil was
investigated [62].
VA-HIT patients with DM or insulin resistance treated with gemfibrozil who
were PPARA Leu162 homozygotes had a greater absolute reduction in
cardiovascular events (12.1% reduction compared to treatment with placebo; P =
.06) compared to carriers of the PPARA Val162 allele who had a nonsignificant
reduction (9.9% compared to treatment with placebo; P = .28) [62].
Furthermore, in VA-HIT patients without DM or insulin resistance, carriers
of the Val162 allele had a significant increase in cardiovascular events in
response to gemfibrozil (7% increase compared to
treatment with placebo; P = .01) [62].


## 2.2.2. Response to Fenofibrate

The Genetics of Lipid Lowering
Drugs and Diet Network  (GOLDN) study
investigated the response to fenofibrate (160 mg) for ≥21 days
in 791 men and women enrolled in The Family Heart Study (FHS, a multicenter, family pedigree study aimed to identify genetic and environmental risk factors of
cardiovascular disease)
[63].
Overall, there was a 37 mg/dL reduction in fasting serum triglyceride
levels after treatment with fenofibrate (the average of two separate
measurements obtained prior to treatment and at the end of treatment were
used).  Although only reported in
abstract form to date, variation in PPARA Leu162Val polymorphism was significantly
associated with fasting triglyceride level response to fenofibrate treatment [64].
Individuals homozygous for the PPARA Val162 allele had a 73 mg/dL
reduction in their fasting triglyceride response to fenofibrate compared to PPARA Leu162Val heterozygotes (46 mg/dL reduction) and PPARA 162Leu homozygotes
(53 mg/dL reduction; P < .0001)
[64].


## 2.3. PPARA Val227Ala Genetic Associations

### 2.3.1. Dyslipidemias

PPARA Val227Ala is a polymorphism located between the DNA binding and ligand binding
domain of PPARα.  This region is thought to be important in heterodimerization
but in vitro experiments confirming a functional difference in alleles have not
yet been performed [65].
The association of the PPARA Val227Ala polymorphism with serum
lipid levels was investigated in a study of 401 healthy Japanese individuals
presenting to medical clinic for routine health care [65]. After adjustment for age and body mass index, female
carriers of the Val227 allele had significantly lower serum total cholesterol (P =
.046) and triglyceride levels (P = .038) compared to Ala227 homozygotes [65].
Male carriers of the Val227 allele also had lower serum total
cholesterol and triglyceride levels compared to Ala227 homozygotes, but the
differences were not significant (P = .30 and .54, resp.) [65].Recently, the finding of this small
study was confirmed in 2899 Chinese individuals from the 1998 Singapore National
Health Survey (NHS98) [66]. Women PPARA Ala227 allele carriers had
significantly lower serum total cholesterol (P = .047) and triglyceride
levels (P = .048), compared to PPARA Val227 homozygotes, and men
had lower levels that were, again, not significant (P = .65 and .12, resp.) [66].
In addition to these findings, this study also found a significant
interaction between the PPARA Val227Ala polymorphism and serum HDL cholesterol
levels in response to dietary polyunsaturated fatty acid intake in women
suggesting a gene-environment interaction (P-value for interaction = .049)
[66].
Specifically, the authors found that, in women who were PPARA Ala227 allele carriers, increasing dietary polyunsaturated fatty acid intake
resulted in lower serum HDL cholesterol levels.
This result was in contrast to male PPARA Ala227 allele carriers,
who had an increase in serum HDL cholesterol levels, and women who were PPARA Val227 homozygotes, who demonstrated less lowering [66].


## 2.3.1. Dyslipidemias

PPARA Val227Ala is a polymorphism located between the DNA binding and ligand binding
domain of PPARα.  This region is thought to be important in heterodimerization
but in vitro experiments confirming a functional difference in alleles have not
yet been performed [65].
The association of the PPARA Val227Ala polymorphism with serum
lipid levels was investigated in a study of 401 healthy Japanese individuals
presenting to medical clinic for routine health care [65]. After adjustment for age and body mass index, female
carriers of the Val227 allele had significantly lower serum total cholesterol (P =
.046) and triglyceride levels (P = .038) compared to Ala227 homozygotes [65].
Male carriers of the Val227 allele also had lower serum total
cholesterol and triglyceride levels compared to Ala227 homozygotes, but the
differences were not significant (P = .30 and .54, resp.) [65].Recently, the finding of this small
study was confirmed in 2899 Chinese individuals from the 1998 Singapore National
Health Survey (NHS98) [66]. Women PPARA Ala227 allele carriers had
significantly lower serum total cholesterol (P = .047) and triglyceride
levels (P = .048), compared to PPARA Val227 homozygotes, and men
had lower levels that were, again, not significant (P = .65 and .12, resp.) [66].
In addition to these findings, this study also found a significant
interaction between the PPARA Val227Ala polymorphism and serum HDL cholesterol
levels in response to dietary polyunsaturated fatty acid intake in women
suggesting a gene-environment interaction (P-value for interaction = .049)
[66].
Specifically, the authors found that, in women who were PPARA Ala227 allele carriers, increasing dietary polyunsaturated fatty acid intake
resulted in lower serum HDL cholesterol levels.
This result was in contrast to male PPARA Ala227 allele carriers,
who had an increase in serum HDL cholesterol levels, and women who were PPARA Val227 homozygotes, who demonstrated less lowering [66].


## 2.4. PPARA IVS7 2498 G > C  Genetic Associations

### 2.4.1. Coronary Atherosclerosis

PPARA IVS7 2498 is a polymorphism located in intron 7 of PPARA.  The functional significance of this
polymorphism has remained elusive but significant clinical associations have
been found with this polymorphism.  In
LOCAT, PPARA IVS7 2498 (designated “PPARA intron 7 G/C
polymorphism” in the publication) C allele carriers had a significantly greater
progression of coronary atherosclerosis compared with GG homozygotes [50].
No pharmacogenetic interaction was noted [50].
When the association of PPARA IVS7 2498 polymorphism with
coronary atherosclerosis was investigated in 3,012 healthy middle-aged men in NPHS2, PPARA IVS7 2498 CC homozygotes showed a trend toward greater incidence
of ischemic events (myocardial infarction (MI) or coronary revascularization)
(HR 1.83; 95% CI 0.96–3.51; P = .07) compared to PPARA IVS7 2498 CG
heterozygotes and PPARA IVS7 2498 GG homozygotes
[50].


### 2.4.2. Left Ventricular Hypertrophy

ThePPARA IVS7 2498 (designated “PPARA intron 7 G/C
polymorphism” in the publication) has also been associated with physiologic
left ventricular hypertrophy in 144 young male British army recruits undergoing
a rigorous ten-week exercise program (mixed upper and lower body strength and
endurance training) [67].
This polymorphism has also been associated with pathologic left
ventricular hypertrophy in 1148 hypertensive men and women enrolled in an
echocardiography substudy of the third monitoring trends and determinants in
cardiovascular disease (MONICA) Augsburg study [67].
In both studies, the PPARA IVS7 2498 C allele was significantly
associated with increased LV
mass index [67].


## 2.4.1. Coronary Atherosclerosis

PPARA IVS7 2498 is a polymorphism located in intron 7 of PPARA.  The functional significance of this
polymorphism has remained elusive but significant clinical associations have
been found with this polymorphism.  In
LOCAT, PPARA IVS7 2498 (designated “PPARA intron 7 G/C
polymorphism” in the publication) C allele carriers had a significantly greater
progression of coronary atherosclerosis compared with GG homozygotes [50].
No pharmacogenetic interaction was noted [50].
When the association of PPARA IVS7 2498 polymorphism with
coronary atherosclerosis was investigated in 3,012 healthy middle-aged men in NPHS2, PPARA IVS7 2498 CC homozygotes showed a trend toward greater incidence
of ischemic events (myocardial infarction (MI) or coronary revascularization)
(HR 1.83; 95% CI 0.96–3.51; P = .07) compared to PPARA IVS7 2498 CG
heterozygotes and PPARA IVS7 2498 GG homozygotes
[50].


## 2.4.2. Left Ventricular Hypertrophy

ThePPARA IVS7 2498 (designated “PPARA intron 7 G/C
polymorphism” in the publication) has also been associated with physiologic
left ventricular hypertrophy in 144 young male British army recruits undergoing
a rigorous ten-week exercise program (mixed upper and lower body strength and
endurance training) [67].
This polymorphism has also been associated with pathologic left
ventricular hypertrophy in 1148 hypertensive men and women enrolled in an
echocardiography substudy of the third monitoring trends and determinants in
cardiovascular disease (MONICA) Augsburg study [67].
In both studies, the PPARA IVS7 2498 C allele was significantly
associated with increased LV
mass index [67].


## 2.5. PPARA IVS7 2498 G > C Pharmacogenetic Associations

### 2.5.1. Response to Fenofibrate

The Diabetes Atherosclerosis Intervention Study
(DAIS) was designed to investigate if fenofibrate treatment of relatively mild
dyslipidemia in 418 patients with type 2 DM would be associated with less progression
of coronary atherosclerosis after treatment for at least 3 years with
fenofibrate [68].
DAIS found that fenofibrate reduced the
progression of angiographic coronary artery disease [69], the progression of
microalbuminuria (an early marker of diabetic nephropathy, and an independent
risk factor for cardiovascular disease) [70]; and although not
powered to examine clinical events, there were fewer in the fenofibrate group compared to the
placebo group [69].  Given these findings, the association between genetic
variation in the PPARA IVS7 2498 polymorphism (designated “PPARA intron 7 G/C polymorphism” in the publication) and response to fenofibrate in
DAIS was investigated [71].
DAIS subjects were divided into high responders (greater than 30%
reduction, chosen because 30% was the mean reduction in DAIS) and low
responders (less than 30% reduction) in their plasma triglyceride levels and the
prevalence of PPARA IVS7 2498 genotype in the two groups was assessed [71].
Of the 85 high responders (55% of population), there was a significantly
different prevalence of PPARA IVS7 2498 GG homozygotes (84.7%) when
compared to the low responders (68.6%; P < .05) [71].
In stepwise logistic regression analysis, the best independent
predictors of response to fenofibrate treatment were baseline triglyceride
level and PPARA IVS7 2498 genotype (PPARA IVS7 2498 GG versus C
allele carriers response to fenofibrate: OR 3.1; 95% CI 1.28–7.52; P = .012)
[71].


### 2.5.2. Response to Acarbose

Investigators from the STOP-NIDDM trial were
interested in whetherPPARA polymorphisms would be associated with the conversion to type 2 DM in response
to acarbose in patients with impaired glucose tolerance [72, 73].
They investigated this association with 11 SNPs located from exon 1 to
exon 8 of PPARA and found that in the
acarbose-treated group, PPARA IVS7 2498 (designated “rs4253778” in the publication) CC
homozygotes had a 2.7-fold risk of developing type 2 DM (95% CI 1.14–6.79; P = .03) [74]. PPARA IVS7 1343 (designated “rs4253776” in the publication), a
SNP located1,155 nucleotides upstream of PPARA IVS7 2498 and in moderate
LD with PPARA IVS7 2498 (r2 of 0.565 in this population),
also had an association with the development of type 2 DM [74]. PPARA IVS7 1343 G allele
carriers had a 1.7-fold increased risk of developing type 2 DM (95% CI 1.04–2.88; P = .04) and a significant
treatment by genotype interaction was observed [74].


## 2.5.1. Response to Fenofibrate

The Diabetes Atherosclerosis Intervention Study
(DAIS) was designed to investigate if fenofibrate treatment of relatively mild
dyslipidemia in 418 patients with type 2 DM would be associated with less progression
of coronary atherosclerosis after treatment for at least 3 years with
fenofibrate [68].
DAIS found that fenofibrate reduced the
progression of angiographic coronary artery disease [69], the progression of
microalbuminuria (an early marker of diabetic nephropathy, and an independent
risk factor for cardiovascular disease) [70]; and although not
powered to examine clinical events, there were fewer in the fenofibrate group compared to the
placebo group [69].  Given these findings, the association between genetic
variation in the PPARA IVS7 2498 polymorphism (designated “PPARA intron 7 G/C polymorphism” in the publication) and response to fenofibrate in
DAIS was investigated [71].
DAIS subjects were divided into high responders (greater than 30%
reduction, chosen because 30% was the mean reduction in DAIS) and low
responders (less than 30% reduction) in their plasma triglyceride levels and the
prevalence of PPARA IVS7 2498 genotype in the two groups was assessed [71].
Of the 85 high responders (55% of population), there was a significantly
different prevalence of PPARA IVS7 2498 GG homozygotes (84.7%) when
compared to the low responders (68.6%; P < .05) [71].
In stepwise logistic regression analysis, the best independent
predictors of response to fenofibrate treatment were baseline triglyceride
level and PPARA IVS7 2498 genotype (PPARA IVS7 2498 GG versus C
allele carriers response to fenofibrate: OR 3.1; 95% CI 1.28–7.52; P = .012)
[71].


## 2.5.2. Response to Acarbose

Investigators from the STOP-NIDDM trial were
interested in whetherPPARA polymorphisms would be associated with the conversion to type 2 DM in response
to acarbose in patients with impaired glucose tolerance [72, 73].
They investigated this association with 11 SNPs located from exon 1 to
exon 8 of PPARA and found that in the
acarbose-treated group, PPARA IVS7 2498 (designated “rs4253778” in the publication) CC
homozygotes had a 2.7-fold risk of developing type 2 DM (95% CI 1.14–6.79; P = .03) [74]. PPARA IVS7 1343 (designated “rs4253776” in the publication), a
SNP located1,155 nucleotides upstream of PPARA IVS7 2498 and in moderate
LD with PPARA IVS7 2498 (r2 of 0.565 in this population),
also had an association with the development of type 2 DM [74]. PPARA IVS7 1343 G allele
carriers had a 1.7-fold increased risk of developing type 2 DM (95% CI 1.04–2.88; P = .04) and a significant
treatment by genotype interaction was observed [74].


## 3.PPARG

### 3.1. PPARG Pro12Ala Genetic Associations

#### 3.1.1. Metabolic Traits and the Development of Type 2 DM

ThePPARG Pro12Ala polymorphism is in
exon B of PPARG which is specific to PPARγ2, the PPARγ isoform restricted to adipose tissue [75]. In vitro experiments have demonstrated that, compared
to the PPARG Pro12 variant, the PPARG Ala12 variant has lower
binding affinity for a PPAR responsive element and decreased PPARγ-activation of a reporter construct in response
to ligand [75].
The PPARG Pro12Ala polymorphism has been the most investigated
PPAR polymorphism.The association of thePPARG Pro12Ala polymorphism with metabolic traits and the risk/development of DM has
been investigated in individuals of all ages and of different ethnicities including
Chinese and Japanese individuals in the Hypertension and Insulin Resistance
(SAPPHIRe) study, [76], Iranian
individuals [77], obese
Italian children, [78]
middle-aged and elderly Finns, [75] and Spanish women [79]. Although most of these studies (including the
ones mentioned here) report that PPARG Ala12 allele carriers have
increased insulin sensitivity compared to PPARG Pro12 homozygotes, a
recent meta-analysis of 57 studies reported that this association only held for
certain subgroups [80]. When PPARG Ala12 allele carriers were
compared to PPARG Pro12 homozygotes, only the obese subgroup demonstrated
increased insulin sensitivity [80].
However, when PPARG Ala12 homozygotes were compared to PPARG Pro12 homozygotes (full genotype information that allowed this analysis was
only available in 12 of the 57 studies), the association of the PPARG Ala12 allele with increased insulin sensitivity was more evident in all groups [80].More recently, the association of thePPARG Pro12Ala polymorphism
with metabolic traits and the risk of developing hyperglycemia over 6 years was
investigated in 3,914 French Caucasians in the Data From an Epidemiological
Study on the Insulin Resistance Syndrome (DESIR) cohort (of note, this study
was not included in the meta-analysis as it was published after the
meta-analysis was submitted) [81].
At baseline, PPARG Ala12 allele carriers had significantly lower
fasting insulin and insulin resistance as determined by homeostasis model
assessment of insulin resistance (P = .001, compared to PPARG Pro12 homozygotes) [81].
After 6 years of follow up, PPARG Ala12 allele carriers had
significantly less increase in fasting insulin (P = .007, compared to PPARG Pro12 homozygotes) and insulin resistance (P = .018, compared to PPARG Pro12 homozygotes) [81].
In addition, after 6 years of follow up, PPARG Ala12 allele
carriers who were normoglycemic at baseline (n = 3,498) had significantly less
hyperglycemia, compared to compared to PPARG Pro12 homozygotes [81].This data, as well as very recent data from 3,548 individuals in the diabetes
prevention program (DPP) [82] confirmed two earlier meta-analyses (of
the literature available at time of each meta-analysis publication) [83, 84]. This large study reported that PPARG Pro12 homozygotes had a 1.2-fold increased risk of developing type 2 DM (95% CI
0.99–1.57; P = .07) compared to PPARG Ala12 allele carriers [85].
This relative risk matched the 1.2-fold risk found in both meta-analyses
(P = .002 in the meta-analysis
performed by Altshuler et al.) [83, 84].


#### 3.1.2. Coronary and Carotid Atherosclerosis

Several studies have investigated the
association of thePPARG Pro12Ala polymorphism with coronary artery
disease and/or myocardial ischemic events, however, some have yielded
contradictory results [86–88].
14,916 men enrolled in the Physicians' Health Study [89] were followed for a mean of 13.2
years and the association between PPARG Pro12Ala polymorphism and MI was
assessed [88]. PPARG Pro12Ala genotype was compared in 523 individuals who developed an MI, and 2,092 who did not show evidence of an MI [88].
Of those individuals who developed an MI, the frequency of PPARG Ala12 allele carriers was significantly less than in the controls, with a
decreased risk of subsequent MI (hazard ratio HR = 0.77; 95% CI 0.60–0.98; P =
.034) [88]. This relationship held even after controlling for traditional cardiac
risk factors.In contrast,
a study of 2,016  patients with type 2 DM from the genetic portion
of the continually updated dataset known as the Diabetes Audit and Research in
Tayside Scotland database (Go-DARTS) [87], a borderline, nonsignificant
association of the PPARG Ala12 allele carriers with nonfatal MI or
revascularization (HR 0.54; 95%CI 0.27–1.08; P = 0.08, compared to PPARG Pro12 homozygotes) was observed for the entire group.  Subgroup analysis demonstrated a significant
association if patients younger than 70 years old at time of enrollment were
assessed separately (HR 0.43; CI 0.18–0.99; P = .05) or if patients
younger than 70 year old at time of enrollment with no prior history of stroke,
MI, or revascularization were evaluated for time to first event (HR 0.21; CI
0.06–0.69; P = .01) [87].When the association ofPPARG Pro12Ala polymorphism with the risk of coronary artery disease was assessed
prospectively in women enrolled in the Nurses' Health Study (8 years mean
follow up) and in men (6 years mean follow up) enrolled in the Health
Professionals Follow-Up Study (HPSF) [86], carriers of the PPARG Ala12
allele again had an increased risk of MI [86].
249 women and 266 men with MI were compared to nested case-controls and matched
for age, smoking status, and phlebotomy date [86].
Men carriers of the PPARG Ala12 allele had an increased risk of
MI or cardiac death (RR = 1.44; CI 1.00–2.07; P = .05) [86].
There was no statistical difference in nonfatal MI or cardiac death in
women carriers of the PPARG Ala12 allele (RR = 1.17; CI 0.82–1.68; P = .39) [86]. When data were pooled for men and women, carriers of the PPARG Ala12
allele had an increase risk of MI or cardiac death (RR = 1.30; CI 1.00–1.67; P =
.05) and, when stratified by body weight, men and women with a body mass index ≥25 kg/m2had a 1.68-fold increase in risk (CI 1.13–2.50; P = .01) [86].A study of 267 Korean individuals (158 males and 109 females) referred for coronary angiography for chest pain, found
no significant association between thePPARG Pro12Ala polymorphism and
prevalence or severity of coronary artery disease [90].
While the results from these studies may seem contradictory, there are
obvious differences in study design, patient cohorts, primary end-points, and
power.  In addition, it is possible that
geographic and ethnic differences in allele frequencies may contribute to
variability in the study findings.An association has also been observed
between thePPARG Pro12Ala polymorphism and carotid intima media
thickness [91, 92].
In two studies involving over 300 patients, carriers of the PPARG Ala12 allele had less carotid intima media thickness measured by B-mode
ultrasound [91, 92].


### 3.2. PPARG Pro12Ala Pharmacogenetic Associations

#### 3.2.1. Response to Rosiglitazone

ThePPARG Pro12Ala polymorphism resides in the ligand binding domain of PPARγ and could therefore result in different
affinity to bind TZDs. Variation in the PPARG Pro12Ala polymorphism and response to rosiglitazone was investigated in 198 men
and women with type 2 DM (HbA1C values between 7.5–11.5% and fasting glucoses between 140–250 mg/dL) treated with rosiglitazone for 12
weeks [93].
The decrease in fasting glucose in response to the drug was
significantly greater in carriers of the PPARG Ala12 allele compared to PPARG Pro12 homozygous patients [93].
Improvement in HbA1C was also significantly better in
carriers of the PPARG Ala12 allele compared to PPARG Pro12
homozygous patients [93].
In addition, 86.67% of PPARG Ala12 allele carriers responded to rosiglitazone
(defined by a greater than 15% decrease in HbA1C levels and/or a
greater than 20% decrease in fasting glucose level) compared to 43.72% of PPARG Pro12 homozygous patients (P = .002) [93].


#### 3.2.2. Response to Acarbose

Investigators from the STOP-NIDDM trial were
interested in whether PPAR polymorphisms would be associated with the
conversion to type 2 DM in response to acarbose in patients with impaired
glucose tolerance [72, 73].  They found that women treated with acarbose
homozygous for the PPARG Pro12 allele had increased risk of developing
type 2 DM compared to PPARG Ala12 allele carriers treated with acarbose
(OR 2.89; 95% CI 1.20–6.96; P = .018) but found no significant difference
in the men [72].
The authors did not provide an explanation
for the gender differences.


### 3.3. PPARG 54,347 C > T Genetic Associations

#### 3.3.1. Coronary Atherosclerosis

ThePPARG 54,347 C > T polymorphism (also referred to as PPARG 161 C > T
and PPARG 14,311 C > T) is a silent C > T substitution (i.e.,
does not cause an amino acid change in the protein) in nucleotide 161 of exon 6
[94].
No functional information on this polymorphism is available to date. The PPARG 54,347 C > T
polymorphism has been associated with the extent of coronary artery disease by
angiography [95], carotid
intima media thickness [92], and incidence of
MI among individuals younger than age 50 [96].


### 3.4. PPARG 54,347 C > T Pharmacogenetic Associations

#### 3.4.1. Response to Fluvastatin

The Lipoprotein and Coronary Atherosclerosis Study (LCAS) was a randomized,
placebo-controlled study of 429 subjects, 35–70 years old, with at least one
30–75% diameter stenosis on coronary angiography and LDL cholesterol of
115–190 mg/dL designed to assess the regression in coronary atherosclerosis (as
measured by within-patient perlesion change in minimal lumen diameter by
quantitative coronary angiography) in response to fluvastatin [97, 98]. After 2.5 years of treatment with fluvastatin,
mean LDL cholesterol was reduced by 23.9%, and change in minimal lumen diameter
by quantitative coronary angiography was significantly less in the fluvastatin-treated
group (0.028 mm decrease in diameter in the fluvastatin-treated group compared
to 0.100 mm decrease in diameter in the placebo group; P < .01) [99]. Clinical event rates had a trend towards
benefit in the fluvastatin-treated group but were not statistically significant
[99].Genetic variation ofPPARG 54,347 C > T (designated “PPARG 161 C > T” in the publication), PPARG Pro12Ala, and PPARG 25,506 C > T as well as the association with baseline
lipid parameters and response to fluvastatin was assessed in 372 individuals
from LCAS [100]. PPARG haplotype was associated
with the degree of
coronary atherosclerosis (mean number of coronary lesions; P =
.026) and changes
in minimum lumen diameter (P = .022) in response to fluvastatin [100]. PPARA and PPARD polymorphisms were also assessed: no
associations were found with PPARA genotype or haplotype; PPARD associations are discussed below [100].


### 3.5. PPARG Haplotype Pharmacogenetic Associations

#### 3.5.1. Response to Troglitazone

The Troglitazone in the Prevention of Diabetes
(TRIPOD) study was a placebo-controlled trial designed to test if TZD therapy
could prevent the development of type 2 DM in Hispanic women with previous
gestational DM [101, 102].  In this trial, the incidence of type 2 DM was
decreased by 55% in the troglitazone-treated group (coincident with improvement
in insulin sensitivity) compared to placebo [102].  Interestingly, 8 months after discontinuation
of treatment, there remained a statistically significant difference in the
development of type 2 DM between those treated with troglitazone and placebo
(2.3% versus 15%; P = .03) [102].In TRIPOD, 30% of women were classified as nonresponders as they were in the
lowest tertile of 3 month improvement in insulin sensitivity and did not gain
any protection from development of type 2 DM [102].    Although there was no association of the
common, functional PPARG Pro12Ala polymorphism with response
to troglitazone [103], there was an individual association
of eight other PPARG polymorphisms with troglitazone response [104].
In addition, three hapolotypes blocks were defined that were independently, or
jointly, involved in mediating the response to troglitazone [104].
Specifically, individuals with the most common haplotype within a
haplotype block starting in intron 1, containing the A2 promoter and ending
within intron 2 (designated “Block 1” in the publication) had an odds ratio of
2.22 for nonresponse to troglitazone (P = .032), and the most common haplotype within a
haplotype, located completely within intron 2 (designated “Block 2” in the publication),
had an odds ratio of 4.18 for nonresponse (P = .012) [104].
In addition, the most common haplotype within a haplotype located in the
3′ untranslated region of PPARG (designated “Block 5” in the publication)
had a borderline significant odds ratio of 0.51 for response (P = .049) [104].


## 3.1. PPARG Pro12Ala Genetic Associations

### 3.1.1. Metabolic Traits and the Development of Type 2 DM

ThePPARG Pro12Ala polymorphism is in
exon B of PPARG which is specific to PPARγ2, the PPARγ isoform restricted to adipose tissue [75]. In vitro experiments have demonstrated that, compared
to the PPARG Pro12 variant, the PPARG Ala12 variant has lower
binding affinity for a PPAR responsive element and decreased PPARγ-activation of a reporter construct in response
to ligand [75].
The PPARG Pro12Ala polymorphism has been the most investigated
PPAR polymorphism.The association of thePPARG Pro12Ala polymorphism with metabolic traits and the risk/development of DM has
been investigated in individuals of all ages and of different ethnicities including
Chinese and Japanese individuals in the Hypertension and Insulin Resistance
(SAPPHIRe) study, [76], Iranian
individuals [77], obese
Italian children, [78]
middle-aged and elderly Finns, [75] and Spanish women [79]. Although most of these studies (including the
ones mentioned here) report that PPARG Ala12 allele carriers have
increased insulin sensitivity compared to PPARG Pro12 homozygotes, a
recent meta-analysis of 57 studies reported that this association only held for
certain subgroups [80]. When PPARG Ala12 allele carriers were
compared to PPARG Pro12 homozygotes, only the obese subgroup demonstrated
increased insulin sensitivity [80].
However, when PPARG Ala12 homozygotes were compared to PPARG Pro12 homozygotes (full genotype information that allowed this analysis was
only available in 12 of the 57 studies), the association of the PPARG Ala12 allele with increased insulin sensitivity was more evident in all groups [80].More recently, the association of thePPARG Pro12Ala polymorphism
with metabolic traits and the risk of developing hyperglycemia over 6 years was
investigated in 3,914 French Caucasians in the Data From an Epidemiological
Study on the Insulin Resistance Syndrome (DESIR) cohort (of note, this study
was not included in the meta-analysis as it was published after the
meta-analysis was submitted) [81].
At baseline, PPARG Ala12 allele carriers had significantly lower
fasting insulin and insulin resistance as determined by homeostasis model
assessment of insulin resistance (P = .001, compared to PPARG Pro12 homozygotes) [81].
After 6 years of follow up, PPARG Ala12 allele carriers had
significantly less increase in fasting insulin (P = .007, compared to PPARG Pro12 homozygotes) and insulin resistance (P = .018, compared to PPARG Pro12 homozygotes) [81].
In addition, after 6 years of follow up, PPARG Ala12 allele
carriers who were normoglycemic at baseline (n = 3,498) had significantly less
hyperglycemia, compared to compared to PPARG Pro12 homozygotes [81].This data, as well as very recent data from 3,548 individuals in the diabetes
prevention program (DPP) [82] confirmed two earlier meta-analyses (of
the literature available at time of each meta-analysis publication) [83, 84]. This large study reported that PPARG Pro12 homozygotes had a 1.2-fold increased risk of developing type 2 DM (95% CI
0.99–1.57; P = .07) compared to PPARG Ala12 allele carriers [85].
This relative risk matched the 1.2-fold risk found in both meta-analyses
(P = .002 in the meta-analysis
performed by Altshuler et al.) [83, 84].


### 3.1.2. Coronary and Carotid Atherosclerosis

Several studies have investigated the
association of thePPARG Pro12Ala polymorphism with coronary artery
disease and/or myocardial ischemic events, however, some have yielded
contradictory results [86–88].
14,916 men enrolled in the Physicians' Health Study [89] were followed for a mean of 13.2
years and the association between PPARG Pro12Ala polymorphism and MI was
assessed [88]. PPARG Pro12Ala genotype was compared in 523 individuals who developed an MI, and 2,092 who did not show evidence of an MI [88].
Of those individuals who developed an MI, the frequency of PPARG Ala12 allele carriers was significantly less than in the controls, with a
decreased risk of subsequent MI (hazard ratio HR = 0.77; 95% CI 0.60–0.98; P =
.034) [88]. This relationship held even after controlling for traditional cardiac
risk factors.In contrast,
a study of 2,016  patients with type 2 DM from the genetic portion
of the continually updated dataset known as the Diabetes Audit and Research in
Tayside Scotland database (Go-DARTS) [87], a borderline, nonsignificant
association of the PPARG Ala12 allele carriers with nonfatal MI or
revascularization (HR 0.54; 95%CI 0.27–1.08; P = 0.08, compared to PPARG Pro12 homozygotes) was observed for the entire group.  Subgroup analysis demonstrated a significant
association if patients younger than 70 years old at time of enrollment were
assessed separately (HR 0.43; CI 0.18–0.99; P = .05) or if patients
younger than 70 year old at time of enrollment with no prior history of stroke,
MI, or revascularization were evaluated for time to first event (HR 0.21; CI
0.06–0.69; P = .01) [87].When the association ofPPARG Pro12Ala polymorphism with the risk of coronary artery disease was assessed
prospectively in women enrolled in the Nurses' Health Study (8 years mean
follow up) and in men (6 years mean follow up) enrolled in the Health
Professionals Follow-Up Study (HPSF) [86], carriers of the PPARG Ala12
allele again had an increased risk of MI [86].
249 women and 266 men with MI were compared to nested case-controls and matched
for age, smoking status, and phlebotomy date [86].
Men carriers of the PPARG Ala12 allele had an increased risk of
MI or cardiac death (RR = 1.44; CI 1.00–2.07; P = .05) [86].
There was no statistical difference in nonfatal MI or cardiac death in
women carriers of the PPARG Ala12 allele (RR = 1.17; CI 0.82–1.68; P = .39) [86]. When data were pooled for men and women, carriers of the PPARG Ala12
allele had an increase risk of MI or cardiac death (RR = 1.30; CI 1.00–1.67; P =
.05) and, when stratified by body weight, men and women with a body mass index ≥25 kg/m2had a 1.68-fold increase in risk (CI 1.13–2.50; P = .01) [86].A study of 267 Korean individuals (158 males and 109 females) referred for coronary angiography for chest pain, found
no significant association between thePPARG Pro12Ala polymorphism and
prevalence or severity of coronary artery disease [90].
While the results from these studies may seem contradictory, there are
obvious differences in study design, patient cohorts, primary end-points, and
power.  In addition, it is possible that
geographic and ethnic differences in allele frequencies may contribute to
variability in the study findings.An association has also been observed
between thePPARG Pro12Ala polymorphism and carotid intima media
thickness [91, 92].
In two studies involving over 300 patients, carriers of the PPARG Ala12 allele had less carotid intima media thickness measured by B-mode
ultrasound [91, 92].


## 3.1.1. Metabolic Traits and the Development of Type 2 DM

ThePPARG Pro12Ala polymorphism is in
exon B of PPARG which is specific to PPARγ2, the PPARγ isoform restricted to adipose tissue [75]. In vitro experiments have demonstrated that, compared
to the PPARG Pro12 variant, the PPARG Ala12 variant has lower
binding affinity for a PPAR responsive element and decreased PPARγ-activation of a reporter construct in response
to ligand [75].
The PPARG Pro12Ala polymorphism has been the most investigated
PPAR polymorphism.The association of thePPARG Pro12Ala polymorphism with metabolic traits and the risk/development of DM has
been investigated in individuals of all ages and of different ethnicities including
Chinese and Japanese individuals in the Hypertension and Insulin Resistance
(SAPPHIRe) study, [76], Iranian
individuals [77], obese
Italian children, [78]
middle-aged and elderly Finns, [75] and Spanish women [79]. Although most of these studies (including the
ones mentioned here) report that PPARG Ala12 allele carriers have
increased insulin sensitivity compared to PPARG Pro12 homozygotes, a
recent meta-analysis of 57 studies reported that this association only held for
certain subgroups [80]. When PPARG Ala12 allele carriers were
compared to PPARG Pro12 homozygotes, only the obese subgroup demonstrated
increased insulin sensitivity [80].
However, when PPARG Ala12 homozygotes were compared to PPARG Pro12 homozygotes (full genotype information that allowed this analysis was
only available in 12 of the 57 studies), the association of the PPARG Ala12 allele with increased insulin sensitivity was more evident in all groups [80].More recently, the association of thePPARG Pro12Ala polymorphism
with metabolic traits and the risk of developing hyperglycemia over 6 years was
investigated in 3,914 French Caucasians in the Data From an Epidemiological
Study on the Insulin Resistance Syndrome (DESIR) cohort (of note, this study
was not included in the meta-analysis as it was published after the
meta-analysis was submitted) [81].
At baseline, PPARG Ala12 allele carriers had significantly lower
fasting insulin and insulin resistance as determined by homeostasis model
assessment of insulin resistance (P = .001, compared to PPARG Pro12 homozygotes) [81].
After 6 years of follow up, PPARG Ala12 allele carriers had
significantly less increase in fasting insulin (P = .007, compared to PPARG Pro12 homozygotes) and insulin resistance (P = .018, compared to PPARG Pro12 homozygotes) [81].
In addition, after 6 years of follow up, PPARG Ala12 allele
carriers who were normoglycemic at baseline (n = 3,498) had significantly less
hyperglycemia, compared to compared to PPARG Pro12 homozygotes [81].This data, as well as very recent data from 3,548 individuals in the diabetes
prevention program (DPP) [82] confirmed two earlier meta-analyses (of
the literature available at time of each meta-analysis publication) [83, 84]. This large study reported that PPARG Pro12 homozygotes had a 1.2-fold increased risk of developing type 2 DM (95% CI
0.99–1.57; P = .07) compared to PPARG Ala12 allele carriers [85].
This relative risk matched the 1.2-fold risk found in both meta-analyses
(P = .002 in the meta-analysis
performed by Altshuler et al.) [83, 84].


## 3.1.2. Coronary and Carotid Atherosclerosis

Several studies have investigated the
association of thePPARG Pro12Ala polymorphism with coronary artery
disease and/or myocardial ischemic events, however, some have yielded
contradictory results [86–88].
14,916 men enrolled in the Physicians' Health Study [89] were followed for a mean of 13.2
years and the association between PPARG Pro12Ala polymorphism and MI was
assessed [88]. PPARG Pro12Ala genotype was compared in 523 individuals who developed an MI, and 2,092 who did not show evidence of an MI [88].
Of those individuals who developed an MI, the frequency of PPARG Ala12 allele carriers was significantly less than in the controls, with a
decreased risk of subsequent MI (hazard ratio HR = 0.77; 95% CI 0.60–0.98; P =
.034) [88]. This relationship held even after controlling for traditional cardiac
risk factors.In contrast,
a study of 2,016  patients with type 2 DM from the genetic portion
of the continually updated dataset known as the Diabetes Audit and Research in
Tayside Scotland database (Go-DARTS) [87], a borderline, nonsignificant
association of the PPARG Ala12 allele carriers with nonfatal MI or
revascularization (HR 0.54; 95%CI 0.27–1.08; P = 0.08, compared to PPARG Pro12 homozygotes) was observed for the entire group.  Subgroup analysis demonstrated a significant
association if patients younger than 70 years old at time of enrollment were
assessed separately (HR 0.43; CI 0.18–0.99; P = .05) or if patients
younger than 70 year old at time of enrollment with no prior history of stroke,
MI, or revascularization were evaluated for time to first event (HR 0.21; CI
0.06–0.69; P = .01) [87].When the association ofPPARG Pro12Ala polymorphism with the risk of coronary artery disease was assessed
prospectively in women enrolled in the Nurses' Health Study (8 years mean
follow up) and in men (6 years mean follow up) enrolled in the Health
Professionals Follow-Up Study (HPSF) [86], carriers of the PPARG Ala12
allele again had an increased risk of MI [86].
249 women and 266 men with MI were compared to nested case-controls and matched
for age, smoking status, and phlebotomy date [86].
Men carriers of the PPARG Ala12 allele had an increased risk of
MI or cardiac death (RR = 1.44; CI 1.00–2.07; P = .05) [86].
There was no statistical difference in nonfatal MI or cardiac death in
women carriers of the PPARG Ala12 allele (RR = 1.17; CI 0.82–1.68; P = .39) [86]. When data were pooled for men and women, carriers of the PPARG Ala12
allele had an increase risk of MI or cardiac death (RR = 1.30; CI 1.00–1.67; P =
.05) and, when stratified by body weight, men and women with a body mass index ≥25 kg/m2had a 1.68-fold increase in risk (CI 1.13–2.50; P = .01) [86].A study of 267 Korean individuals (158 males and 109 females) referred for coronary angiography for chest pain, found
no significant association between thePPARG Pro12Ala polymorphism and
prevalence or severity of coronary artery disease [90].
While the results from these studies may seem contradictory, there are
obvious differences in study design, patient cohorts, primary end-points, and
power.  In addition, it is possible that
geographic and ethnic differences in allele frequencies may contribute to
variability in the study findings.An association has also been observed
between thePPARG Pro12Ala polymorphism and carotid intima media
thickness [91, 92].
In two studies involving over 300 patients, carriers of the PPARG Ala12 allele had less carotid intima media thickness measured by B-mode
ultrasound [91, 92].


## 3.2. PPARG Pro12Ala Pharmacogenetic Associations

### 3.2.1. Response to Rosiglitazone

ThePPARG Pro12Ala polymorphism resides in the ligand binding domain of PPARγ and could therefore result in different
affinity to bind TZDs. Variation in the PPARG Pro12Ala polymorphism and response to rosiglitazone was investigated in 198 men
and women with type 2 DM (HbA1C values between 7.5–11.5% and fasting glucoses between 140–250 mg/dL) treated with rosiglitazone for 12
weeks [93].
The decrease in fasting glucose in response to the drug was
significantly greater in carriers of the PPARG Ala12 allele compared to PPARG Pro12 homozygous patients [93].
Improvement in HbA1C was also significantly better in
carriers of the PPARG Ala12 allele compared to PPARG Pro12
homozygous patients [93].
In addition, 86.67% of PPARG Ala12 allele carriers responded to rosiglitazone
(defined by a greater than 15% decrease in HbA1C levels and/or a
greater than 20% decrease in fasting glucose level) compared to 43.72% of PPARG Pro12 homozygous patients (P = .002) [93].


### 3.2.2. Response to Acarbose

Investigators from the STOP-NIDDM trial were
interested in whether PPAR polymorphisms would be associated with the
conversion to type 2 DM in response to acarbose in patients with impaired
glucose tolerance [72, 73].  They found that women treated with acarbose
homozygous for the PPARG Pro12 allele had increased risk of developing
type 2 DM compared to PPARG Ala12 allele carriers treated with acarbose
(OR 2.89; 95% CI 1.20–6.96; P = .018) but found no significant difference
in the men [72].
The authors did not provide an explanation
for the gender differences.


## 3.2.1. Response to Rosiglitazone

ThePPARG Pro12Ala polymorphism resides in the ligand binding domain of PPARγ and could therefore result in different
affinity to bind TZDs. Variation in the PPARG Pro12Ala polymorphism and response to rosiglitazone was investigated in 198 men
and women with type 2 DM (HbA1C values between 7.5–11.5% and fasting glucoses between 140–250 mg/dL) treated with rosiglitazone for 12
weeks [93].
The decrease in fasting glucose in response to the drug was
significantly greater in carriers of the PPARG Ala12 allele compared to PPARG Pro12 homozygous patients [93].
Improvement in HbA1C was also significantly better in
carriers of the PPARG Ala12 allele compared to PPARG Pro12
homozygous patients [93].
In addition, 86.67% of PPARG Ala12 allele carriers responded to rosiglitazone
(defined by a greater than 15% decrease in HbA1C levels and/or a
greater than 20% decrease in fasting glucose level) compared to 43.72% of PPARG Pro12 homozygous patients (P = .002) [93].


## 3.2.2. Response to Acarbose

Investigators from the STOP-NIDDM trial were
interested in whether PPAR polymorphisms would be associated with the
conversion to type 2 DM in response to acarbose in patients with impaired
glucose tolerance [72, 73].  They found that women treated with acarbose
homozygous for the PPARG Pro12 allele had increased risk of developing
type 2 DM compared to PPARG Ala12 allele carriers treated with acarbose
(OR 2.89; 95% CI 1.20–6.96; P = .018) but found no significant difference
in the men [72].
The authors did not provide an explanation
for the gender differences.


## 3.3. PPARG 54,347 C > T Genetic Associations

### 3.3.1. Coronary Atherosclerosis

ThePPARG 54,347 C > T polymorphism (also referred to as PPARG 161 C > T
and PPARG 14,311 C > T) is a silent C > T substitution (i.e.,
does not cause an amino acid change in the protein) in nucleotide 161 of exon 6
[94].
No functional information on this polymorphism is available to date. The PPARG 54,347 C > T
polymorphism has been associated with the extent of coronary artery disease by
angiography [95], carotid
intima media thickness [92], and incidence of
MI among individuals younger than age 50 [96].


## 3.3.1. Coronary Atherosclerosis

ThePPARG 54,347 C > T polymorphism (also referred to as PPARG 161 C > T
and PPARG 14,311 C > T) is a silent C > T substitution (i.e.,
does not cause an amino acid change in the protein) in nucleotide 161 of exon 6
[94].
No functional information on this polymorphism is available to date. The PPARG 54,347 C > T
polymorphism has been associated with the extent of coronary artery disease by
angiography [95], carotid
intima media thickness [92], and incidence of
MI among individuals younger than age 50 [96].


## 3.4. PPARG 54,347 C > T Pharmacogenetic Associations

### 3.4.1. Response to Fluvastatin

The Lipoprotein and Coronary Atherosclerosis Study (LCAS) was a randomized,
placebo-controlled study of 429 subjects, 35–70 years old, with at least one
30–75% diameter stenosis on coronary angiography and LDL cholesterol of
115–190 mg/dL designed to assess the regression in coronary atherosclerosis (as
measured by within-patient perlesion change in minimal lumen diameter by
quantitative coronary angiography) in response to fluvastatin [97, 98]. After 2.5 years of treatment with fluvastatin,
mean LDL cholesterol was reduced by 23.9%, and change in minimal lumen diameter
by quantitative coronary angiography was significantly less in the fluvastatin-treated
group (0.028 mm decrease in diameter in the fluvastatin-treated group compared
to 0.100 mm decrease in diameter in the placebo group; P < .01) [99]. Clinical event rates had a trend towards
benefit in the fluvastatin-treated group but were not statistically significant
[99].Genetic variation ofPPARG 54,347 C > T (designated “PPARG 161 C > T” in the publication), PPARG Pro12Ala, and PPARG 25,506 C > T as well as the association with baseline
lipid parameters and response to fluvastatin was assessed in 372 individuals
from LCAS [100]. PPARG haplotype was associated
with the degree of
coronary atherosclerosis (mean number of coronary lesions; P =
.026) and changes
in minimum lumen diameter (P = .022) in response to fluvastatin [100]. PPARA and PPARD polymorphisms were also assessed: no
associations were found with PPARA genotype or haplotype; PPARD associations are discussed below [100].


## 3.4.1. Response to Fluvastatin

The Lipoprotein and Coronary Atherosclerosis Study (LCAS) was a randomized,
placebo-controlled study of 429 subjects, 35–70 years old, with at least one
30–75% diameter stenosis on coronary angiography and LDL cholesterol of
115–190 mg/dL designed to assess the regression in coronary atherosclerosis (as
measured by within-patient perlesion change in minimal lumen diameter by
quantitative coronary angiography) in response to fluvastatin [97, 98]. After 2.5 years of treatment with fluvastatin,
mean LDL cholesterol was reduced by 23.9%, and change in minimal lumen diameter
by quantitative coronary angiography was significantly less in the fluvastatin-treated
group (0.028 mm decrease in diameter in the fluvastatin-treated group compared
to 0.100 mm decrease in diameter in the placebo group; P < .01) [99]. Clinical event rates had a trend towards
benefit in the fluvastatin-treated group but were not statistically significant
[99].Genetic variation ofPPARG 54,347 C > T (designated “PPARG 161 C > T” in the publication), PPARG Pro12Ala, and PPARG 25,506 C > T as well as the association with baseline
lipid parameters and response to fluvastatin was assessed in 372 individuals
from LCAS [100]. PPARG haplotype was associated
with the degree of
coronary atherosclerosis (mean number of coronary lesions; P =
.026) and changes
in minimum lumen diameter (P = .022) in response to fluvastatin [100]. PPARA and PPARD polymorphisms were also assessed: no
associations were found with PPARA genotype or haplotype; PPARD associations are discussed below [100].


## 3.5. PPARG Haplotype Pharmacogenetic Associations

### 3.5.1. Response to Troglitazone

The Troglitazone in the Prevention of Diabetes
(TRIPOD) study was a placebo-controlled trial designed to test if TZD therapy
could prevent the development of type 2 DM in Hispanic women with previous
gestational DM [101, 102].  In this trial, the incidence of type 2 DM was
decreased by 55% in the troglitazone-treated group (coincident with improvement
in insulin sensitivity) compared to placebo [102].  Interestingly, 8 months after discontinuation
of treatment, there remained a statistically significant difference in the
development of type 2 DM between those treated with troglitazone and placebo
(2.3% versus 15%; P = .03) [102].In TRIPOD, 30% of women were classified as nonresponders as they were in the
lowest tertile of 3 month improvement in insulin sensitivity and did not gain
any protection from development of type 2 DM [102].    Although there was no association of the
common, functional PPARG Pro12Ala polymorphism with response
to troglitazone [103], there was an individual association
of eight other PPARG polymorphisms with troglitazone response [104].
In addition, three hapolotypes blocks were defined that were independently, or
jointly, involved in mediating the response to troglitazone [104].
Specifically, individuals with the most common haplotype within a
haplotype block starting in intron 1, containing the A2 promoter and ending
within intron 2 (designated “Block 1” in the publication) had an odds ratio of
2.22 for nonresponse to troglitazone (P = .032), and the most common haplotype within a
haplotype, located completely within intron 2 (designated “Block 2” in the publication),
had an odds ratio of 4.18 for nonresponse (P = .012) [104].
In addition, the most common haplotype within a haplotype located in the
3′ untranslated region of PPARG (designated “Block 5” in the publication)
had a borderline significant odds ratio of 0.51 for response (P = .049) [104].


## 3.5.1. Response to Troglitazone

The Troglitazone in the Prevention of Diabetes
(TRIPOD) study was a placebo-controlled trial designed to test if TZD therapy
could prevent the development of type 2 DM in Hispanic women with previous
gestational DM [101, 102].  In this trial, the incidence of type 2 DM was
decreased by 55% in the troglitazone-treated group (coincident with improvement
in insulin sensitivity) compared to placebo [102].  Interestingly, 8 months after discontinuation
of treatment, there remained a statistically significant difference in the
development of type 2 DM between those treated with troglitazone and placebo
(2.3% versus 15%; P = .03) [102].In TRIPOD, 30% of women were classified as nonresponders as they were in the
lowest tertile of 3 month improvement in insulin sensitivity and did not gain
any protection from development of type 2 DM [102].    Although there was no association of the
common, functional PPARG Pro12Ala polymorphism with response
to troglitazone [103], there was an individual association
of eight other PPARG polymorphisms with troglitazone response [104].
In addition, three hapolotypes blocks were defined that were independently, or
jointly, involved in mediating the response to troglitazone [104].
Specifically, individuals with the most common haplotype within a
haplotype block starting in intron 1, containing the A2 promoter and ending
within intron 2 (designated “Block 1” in the publication) had an odds ratio of
2.22 for nonresponse to troglitazone (P = .032), and the most common haplotype within a
haplotype, located completely within intron 2 (designated “Block 2” in the publication),
had an odds ratio of 4.18 for nonresponse (P = .012) [104].
In addition, the most common haplotype within a haplotype located in the
3′ untranslated region of PPARG (designated “Block 5” in the publication)
had a borderline significant odds ratio of 0.51 for response (P = .049) [104].


## 4.PPARD

### 4.1. PPARD −87 T > C Genetic Associations

#### 4.1.1. Dyslipidemias

ThePPARD −87 T > C (designated “PPARD 294 T > C” polymorphism in the
publication) was one of four polymorphisms identified by direct sequencing of
the 5′ untranslated region of PPARD in 20 unrelated healthy subjects [105].
This polymorphism is located 87 base pairs upstream of the translation
start site and 294 base pairs downstream from the transcription start
site.  In vitro experiments have
demonstrated functional differences of the two variants and have implicated the
transcriptional corepressor SP1 in contributing to the differences [106].When the association of thePPARD −87 T > C polymorphism with variation in plasma lipid levels was investigated
in 543 healthy men (and validated in an independent cohort of 282 healthy men), PPARD −87 CC homozygotes had increased plasma LDL cholesterol compared
to PPARD −87 TT homozygotes [106].


#### 4.1.2. Coronary Atherosclerosis and Cardiac Events

Skogsberg et al. investigated whether thePPARD −87
T > C polymorphism (designated “PPARD 294 T > C” polymorphism in the
publication) was associated with increased plasma-LDL cholesterol levels
and/or  increased risk of having cardiac
events. In the West Of Scotland Coronary Prevention Study (WOSCOPS), a
randomized, double-blind, placebo-controlled trial with the primary goal of
investigating the effect of pravastatin in preventing cardiac events in
patients with mild-to-moderate
hypercholesterolemia  (LDL cholesterol
between  4.5  and 6.0 mmol/L)
[107].
Although carriers of the PPARD −87 C allele had a significantly
lower HDL cholesterol compared with the PPARD −87 TT homozygotes, there was no
association of this polymorphism with cardiac events and no
genotype-by-treatment interaction [107].


### 4.2. PPARD Haplotype Pharmacogenetic Associations

#### 4.2.1. Response to Fluvastatin

Genetic variation ofPPARD −87 T > C (designated “PPARD 294 T > C” in
the publication) and PPARD −4401 C > T as well as the association with
baseline lipid parameters and response to fluvastatin was assessed in 372
individuals from LCAS [100]. PPARD haplotype was associated with the degree of
coronary atherosclerosis (mean number of coronary lesions) and
changes in triglyceride (P = .01) and apoC-III (P = .047) levels in
response to fluvastatin [100].


#### 4.2.2. Response to Acarbose

Genetic variation in six SNPs inPPARD in
patients with impaired glucose tolerance and association with the conversion to
type 2 DM in response to acarbose was investigated in the STOP-NIDDM trial [72, 73].  Women treated with acarbose carrying the C
allele of PPARD −48,444 C > T (designated “rs6902123” in the
publication) had increased risk of developing type 2 DM compared to TT
homozygous women  treated with acarbose
(OR 2.70; 95% CI 1.44–5.30; adjusted P = .002) [73].


## 4.1. PPARD −87 T > C Genetic Associations

### 4.1.1. Dyslipidemias

ThePPARD −87 T > C (designated “PPARD 294 T > C” polymorphism in the
publication) was one of four polymorphisms identified by direct sequencing of
the 5′ untranslated region of PPARD in 20 unrelated healthy subjects [105].
This polymorphism is located 87 base pairs upstream of the translation
start site and 294 base pairs downstream from the transcription start
site.  In vitro experiments have
demonstrated functional differences of the two variants and have implicated the
transcriptional corepressor SP1 in contributing to the differences [106].When the association of thePPARD −87 T > C polymorphism with variation in plasma lipid levels was investigated
in 543 healthy men (and validated in an independent cohort of 282 healthy men), PPARD −87 CC homozygotes had increased plasma LDL cholesterol compared
to PPARD −87 TT homozygotes [106].


### 4.1.2. Coronary Atherosclerosis and Cardiac Events

Skogsberg et al. investigated whether thePPARD −87
T > C polymorphism (designated “PPARD 294 T > C” polymorphism in the
publication) was associated with increased plasma-LDL cholesterol levels
and/or  increased risk of having cardiac
events. In the West Of Scotland Coronary Prevention Study (WOSCOPS), a
randomized, double-blind, placebo-controlled trial with the primary goal of
investigating the effect of pravastatin in preventing cardiac events in
patients with mild-to-moderate
hypercholesterolemia  (LDL cholesterol
between  4.5  and 6.0 mmol/L)
[107].
Although carriers of the PPARD −87 C allele had a significantly
lower HDL cholesterol compared with the PPARD −87 TT homozygotes, there was no
association of this polymorphism with cardiac events and no
genotype-by-treatment interaction [107].


## 4.1.1. Dyslipidemias

ThePPARD −87 T > C (designated “PPARD 294 T > C” polymorphism in the
publication) was one of four polymorphisms identified by direct sequencing of
the 5′ untranslated region of PPARD in 20 unrelated healthy subjects [105].
This polymorphism is located 87 base pairs upstream of the translation
start site and 294 base pairs downstream from the transcription start
site.  In vitro experiments have
demonstrated functional differences of the two variants and have implicated the
transcriptional corepressor SP1 in contributing to the differences [106].When the association of thePPARD −87 T > C polymorphism with variation in plasma lipid levels was investigated
in 543 healthy men (and validated in an independent cohort of 282 healthy men), PPARD −87 CC homozygotes had increased plasma LDL cholesterol compared
to PPARD −87 TT homozygotes [106].


## 4.1.2. Coronary Atherosclerosis and Cardiac Events

Skogsberg et al. investigated whether thePPARD −87
T > C polymorphism (designated “PPARD 294 T > C” polymorphism in the
publication) was associated with increased plasma-LDL cholesterol levels
and/or  increased risk of having cardiac
events. In the West Of Scotland Coronary Prevention Study (WOSCOPS), a
randomized, double-blind, placebo-controlled trial with the primary goal of
investigating the effect of pravastatin in preventing cardiac events in
patients with mild-to-moderate
hypercholesterolemia  (LDL cholesterol
between  4.5  and 6.0 mmol/L)
[107].
Although carriers of the PPARD −87 C allele had a significantly
lower HDL cholesterol compared with the PPARD −87 TT homozygotes, there was no
association of this polymorphism with cardiac events and no
genotype-by-treatment interaction [107].


## 4.2. PPARD Haplotype Pharmacogenetic Associations

### 4.2.1. Response to Fluvastatin

Genetic variation ofPPARD −87 T > C (designated “PPARD 294 T > C” in
the publication) and PPARD −4401 C > T as well as the association with
baseline lipid parameters and response to fluvastatin was assessed in 372
individuals from LCAS [100]. PPARD haplotype was associated with the degree of
coronary atherosclerosis (mean number of coronary lesions) and
changes in triglyceride (P = .01) and apoC-III (P = .047) levels in
response to fluvastatin [100].


### 4.2.2. Response to Acarbose

Genetic variation in six SNPs inPPARD in
patients with impaired glucose tolerance and association with the conversion to
type 2 DM in response to acarbose was investigated in the STOP-NIDDM trial [72, 73].  Women treated with acarbose carrying the C
allele of PPARD −48,444 C > T (designated “rs6902123” in the
publication) had increased risk of developing type 2 DM compared to TT
homozygous women  treated with acarbose
(OR 2.70; 95% CI 1.44–5.30; adjusted P = .002) [73].


## 4.2.1. Response to Fluvastatin

Genetic variation ofPPARD −87 T > C (designated “PPARD 294 T > C” in
the publication) and PPARD −4401 C > T as well as the association with
baseline lipid parameters and response to fluvastatin was assessed in 372
individuals from LCAS [100]. PPARD haplotype was associated with the degree of
coronary atherosclerosis (mean number of coronary lesions) and
changes in triglyceride (P = .01) and apoC-III (P = .047) levels in
response to fluvastatin [100].


## 4.2.2. Response to Acarbose

Genetic variation in six SNPs inPPARD in
patients with impaired glucose tolerance and association with the conversion to
type 2 DM in response to acarbose was investigated in the STOP-NIDDM trial [72, 73].  Women treated with acarbose carrying the C
allele of PPARD −48,444 C > T (designated “rs6902123” in the
publication) had increased risk of developing type 2 DM compared to TT
homozygous women  treated with acarbose
(OR 2.70; 95% CI 1.44–5.30; adjusted P = .002) [73].


## 5. Conclusions

With their pleiotropic effects on
lipid metabolism, glucose homeostasis, myocardial energetics, and responses to
ischemia, as well as the considerable evidence linking genetic polymorphisms
identified within the PPAR complex to common cardiovascular diseases, the PPAR
family of transcription factors is central to the regulation of a number of key
cellular pathways that impact on normal and pathologic cardiovascular
physiology and thus represent very promising targets for further advances in
pharmacologic intervention.  Early
pharmacogenetic investigations into the associations of a select few of these
polymorphisms with patient responses to drug therapy have yielded important
clues to commonly observed variability in both response and outcomes.  Given the central role of the PPARs in
critical metabolic pathways, this experience points the way to a future where
knowledge of relevant PPAR genotype might be utilized to guide more appropriately
tailored and individualized therapy.



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*Source: 374549-2008-03-24.xml*