# Genetic Epidemiology of Type 2 Diabetes in Mexican Mestizos

Authors: Eiralí Guadalupe García-Chapa; Evelia Leal-Ugarte; Valeria Peralta-Leal; Jorge Durán-González; Juan Pablo Meza-Espinoza
Journal: BioMed Research International
 (2017)

---

## Abstract

There are currently about 415 million people with diabetes worldwide, a figure likely to increase to 642 million by 2040. In 2015, Mexico was the second Latin American country and sixth in the world in prevalence of this disorder with nearly 11.5 million of patients. Type 2 diabetes (T2D) is the main kind of diabetes and its etiology is complex with environmental and genetic factors involved. Indeed, polymorphisms in several genes have been associated with this disease worldwide. To estimate the genetic epidemiology of T2D in Mexican mestizos a systematic bibliographic search of published articles through PubMed, Scopus, Google Scholar, and Web of Science was conducted. Just case-control studies of candidate genes about T2D in Mexican mestizo inhabitants were included. Nineteen studies that met the inclusion criteria were found. In total, 68 polymorphisms of 41 genes were assessed; 26 of them were associated with T2D risk, which were located inABCA1, ADRB3, CAPN10, CDC123/CAMK1D, CDKAL1, CDKN2A/2B, CRP, ELMO1, FTO, HHEX, IGF2BP2, IRS1, JAZF1, KCNQ1, LOC387761, LTA, NXPH1, SIRT1, SLC30A8, TCF7L2,andTNF-α genes. Overall, 21 of the 41 analyzed genes were associated with T2D in Mexican mestizos. Such a genetic heterogeneity compares with findings in other ethnic groups.


---

## Body

## 1. Introduction

Type 2 diabetes (T2D) is a metabolic disorder characterized by impaired glucose uptake in muscle and fat, altered glucose-induced insulin secretion, and increased hepatic glucose production, which lead to hyperglycemia. It is the most common type of diabetes and generally occurs in adults [1]. According to the International Diabetes Federation there are currently around 415 million people with diabetes worldwide, a figure likely to increase to 642 million by 2040 [2]. This disorder accounts for high morbidity and mortality due to complications like renal failure, blindness, amputations, cardiovascular disease, and cerebrovascular events [1]. In 2015 there were approximately 5.0 million deaths by diabetes worldwide [2]. With about 7.3 million patients in 2010 [3], our country was second in Latin America and tenth in the world in prevalence of this disorder [4]. Five years later, the number of diabetic patients was estimated to be 11.5 million and our country ranked sixth in the world [2]. In 2011 most frequent morbidities by T2D were renal failure (24.2%) and peripheral circulatory complications (17.3%), and the mortality rate was 70/100,000 inhabitants (http://fmdiabetes.org/wp-content/uploads/2014/11/diabetes2013INEGI.pdf). The complex etiology of T2D includes factors that influence the risk and evolution of the disease, such as ethnicity, poor alimentation, sedentary lifestyle, obesity, dyslipidemia, and family history [1, 5]. Regarding genetics, worldwide researches have shown association of this disease with numerous allelic variants of nearly 80 candidate genes [6]. The aim of this study is to carry out a literature review about genetic researches conducted in Mexican mestizos for a better understanding of the genetic epidemiology of T2D in our population.


## 2. Methods

A systematic search was done through PubMed, Scopus, Google Scholar, and Web of Science for genetic studies conducted in Mexican mestizo inhabitants with T2D. Key words derived from the phrase “Genetic polymorphisms associated with Diabetes Mellitus type 2 in Mexico, Mexican patients and/or Mexican mestizo” were used. Related terms such as “variants”, “alleles”, and “SNP associated with diabetes, T2DM, or T2D” complemented our search. Just case-control studies of candidate genes performed in Mexican mestizos resident in the country were included. Researches conducted in Mexican native populations were excluded, as well as those done in patients with metabolic syndrome. In surveys that included both patients with metabolic syndrome and patients with T2D, only cases with T2D were registered. Although in the selected studies different models of genotype analyses were used (recessive, dominant, or codominant), solely comparisons between allele frequencies were considered in our review. In studies without described odds ratio (OR), unadjusted OR were estimated from the reported allele or genotype frequencies. Allele comparisons were performed by 2 × 2 contingency tables [Yates’ correction chi-square test (http://vassarstats.net/odds2x2.html)] and genotypes were contrasted by chi-square test (https://ihg.gsf.de/cgi-bin/hw/hwa2.pl). In both comparisons, OR were estimated using 95% confidence intervals (95% CI). A p≤0.05 defined a significant association.Whenever a polymorphism was analyzed in different studies, data were combined and unadjusted OR for alleles were calculated using a 2 × 2 contingency table (Yates’ correction chi-square test). However, studies with suspicion of overlapping of patients were not included in this analysis.


## 3. Results

In total, 19 case-control studies on the possible association of genetic polymorphisms with T2D in Mexican mestizos resident in the country were included [7–25]. Altogether, 68 polymorphisms of 41 genes were assessed (Table 1). Of them, 25 were associated with an increased risk for T2D and they were located in 20 genes, namely,ABCA1, ADRB3, CAPN10, CDC123/CAMK1D, CDKN2A/2B, CRP, ELMO1, FTO, HHEX, IGF2BP2, IRS1, JAZF1, KCNQ1, LOC387761, LTA, NXPH1, SIRT1, SLC30A8, TCF7L2,andTNF-α. Among the variants that showed association there were 4/20 amino acid substitutions, 13/30 intronic sites, 6/10 of promoter region or 5′-flanking region or upstream of gene, 1/2 intergenic regions, and 2/6 of 3′-untranslated or 3′-flanking region of gene. On the other hand, 12 polymorphisms were analyzed by different authors, and concordance was observed in most of them, except for rs3842570(CAPN10) [11, 13, 14], rs13266634(SLC30A4) [8, 17], rs7903146(TCF7L2) [8, 10, 12, 22], and rs1800629(TNF-α) [20, 24, 25]. Eleven of these polymorphisms were pooled and analyzed as shown in Table 2. Note that rs4994(ADRB3) was discarded of this analysis (suspicion of overlap of [9, 10]). Similarly, data by Cruz et al. [10] for rs7903146 and rs12255372 ofTCF7L2 were not considered (possible overlapping with the study by Martínez-Gómez et al. [12]). Thus, the 3R allele of rs3842570, which was associated with T2D in a small sample, did not seemingly confer susceptibility to the disease; in contrast, the C allele of rs7754840(CDKAL1), which evidenced no risk in independent studies, showed association with T2D. Including this allele, a total of 26 polymorphisms and 21 genes were associated with T2D in Mexican mestizos.Table 1
Analyzed genes in studies about type 2 diabetes conducted in Mexican mestizos.
Gene
Chrom
dbSNP loc
Change
Effect
n
a; nb
OR (95% CI)
p
Reference
ABCA1
9q31
rs9282541
C/T
R/C
244; 202
2.50 (1.48–4.24)
0.001
[7]
rs2000069
C/T
Intronic
244; 202
1.08 (0.82–1.42)c
0.58
[7]
rs2230806
G/A
R/K
244; 202
1.17 (0.89–1.55)c
0.27
[7]
rs2487037
C/T
Intronic
244; 202
1.06 (0.79–1.43)c
0.71
[7]
rs3818689
G/C
Intronic
244; 202
0.94 (0.52–1.68)c
0.82
[7]
ADAMTS9
3p14
rs4607103
C/T
Intronic
1027; 990
1.05 (0.91–1.20)d
0.521
[8]
ADRB1
10q25
rs1801253
C/G
R/G
501; 552
0.79 (0.61–1.02)c
0.07
[9]
ADRB3
8p11
rs4994
C/T
W/R
519; 547
1.69 (1.37–2.09)
c
0.0001
[10]
rs4994
C/T
W/R
501; 552
1.34 (1.10–1.64)
c
0.004
[9]
ARHGEF11
1q21
rs945508
G/A
R/H
868; 504
0.91 (0.76–1.09)e
0.319
[8]
CAPN10
2q37
rs3792267
G/A
Intronic
132; 112
0.97 (0.66–1.42)c
0.86
[11]
rs3792267
G/A
Intronic
719; 746
1.11 (0.95–1.29)c,f
0.20
[12]
rs3792267
G/A
Intronic
211; 152
0.91 (0.66–1.26)
0.56
[13]
rs3842570
2R/3R
Intronic
132; 112
0.97 (0.68–1.40)c
0.89
[11]
rs3842570
2R/3R
Intronic
43; 64
1.81 (1.03–3.18)
c
0.038
[14]
rs3842570
2R/3R
Intronic
211; 152
0.75 (0.55–1.02)
0.06
[13]
rs5030952
C/T
Intronic
132; 113
0.85 (0.56–1.29)c
0.45
[11]
rs5030952
C/T
Intronic
211; 152
1.35 (0.89–2.06)
0.16
[13]
rs2975760
T/C
Intronic
134; 113
2.72 (1.16–6.35)
0.017
[11]
CAPN10
2q37
rs7607759
A/G
T/A
127; 110
2.27 (0.98–5.25)c
0.051
[11]
CDC123/CAMK1D
10p13
rs12779790
A/G
Intergenic
1027; 990
1.24 (1.05–1.47)
d
0.013
[8]
CDKAL1
6p22
rs10946398
A/C
Intronic
519; 547
1.09 (0.91–1.32)c
0.337
[10]
rs9465871
C/T
Intronic
519; 547
1.04 (0.85–1.26)c
0.718
[10]
rs7754840
C/G
Intronic
519; 547
1.08 (0.89–1.29)c
0.438
[10]
rs7754840
C/G
Intronic
1027; 990
1.13 (0.98–1.30)d,g
0.081
[8]
CDKN2A/2B
9p21
rs10811661
C/T
Upstream
1027; 990
1.42 (1.15–1.75)
d
0.001
[8]
CRP
1q23
rs1130864
C/T
3′-UTR
166; 130
1.59 (1.15–2.22)
c
,
h
,
i
0.005
[15]
rs1205
G/A
3′-UTR
166; 130
0.82 (0.59–1.14)c,h,i
0.24
[15]
rs2794521
A/G
5′-flanking
166; 130
1.97 (1.15–3.38)
c
,
h
,
i
0.012
[15]
rs3093062
G/A
Promoter
166; 130
3.49 (0.98–12.4)
c
,
h
,
i
0.039
[15]
ELMO1
7p14
rs1345365
A/G
Intronic
148; 269
1.37 (1.02–1.84)
c
,
h
,
i
0.035
[16]
ENPP1
6q23
rs1044498
A/C
K/Q
519; 547
0.94 (0.76–1.16)c
0.577
[10]
EXT2
11p11
rs3740878
A/G
Intronic
455; 234
0.83 (0.65–1.05)
0.054
[17]
FTO
16q12
rs8050136
A/C
Intronic
868; 504
0.90 (0.74–1.09)e
0.278
[8]
rs9939609
A/T
Intronic
519; 547
1.25 (1.02–1.54)
c
0.027
[10]
HHEX
10q23
rs5015480
C/T
Upstream
519; 547
0.96 (0.80–1.14)c
0.631
[10]
rs1111875
C/T
3′-flanking
1027; 990
1.01 (0.89–1.16)d
0.859
[8]
rs1111875
C/T
3′-flanking
455; 234
1.12 (0.88–1.44)
0.27
[17]
HHEX
10q23
rs7923837
A/G
3′-flanking
868; 504
1.21 (1.02–1.44)
k
0.025
[8]
HMOX1
22q12
rs2071749
A/G
Promoter
614; 956
0.98 (0.84–1.14)c
0.76
[18]
IGF2BP2
3q27
rs4402960
G/T
Intronic
868; 504
1.24 (1.01–1.53)
j
0.042
[8]
IRS1
2q36
rs1801278
G/A
G/R
719; 746
2.04 (1.41–2.96)
c
,
f
<0.001
[12]
rs1801278
G/A
G/R
444; 444
3.22 (1.99–5.20)
0.001
[19]
rs1801276
C/G
P/A
444; 444
0.98 (0.72–1.32)
0.83
[19]
rs3731594
G/A
N/D
444; 444
0.83 (0.42–1.66)
0.47
[19]
rs1801108
G/C
R/P
444; 444
1.07 (0.85–1.34)
0.40
[19]
JAZF1
7p15
rs864745
T/C
Intronic
868; 504
1.24 (1.04–1.47)
k
0.015
[8]
KCNJ11
11p15
rs5215
C/T
V/I
519; 547
1.03 (0.87–1.23)c
0.729
[10]
rs5210
A/G
3′-UTR
519; 547
1.03 (0.86–1.23)c
0.764
[10]
rs5219
C/T
E/K
1027; 990
1.10 (0.96–1.26)d
0.154
[8]
KCNQ1
11p15
rs2237892
C/T
Intronic
868; 504
1.36 (1.13–1.64)
k
0.001
[8]
LEPR
1p31
rs1137100
A/G
K/R
519; 547
1.00 (0.84–1.21)c
0.92
[10]
LOC387761
11p12
rs7480010
A/G
Intronic
455; 234
1.43 (1.05–1.94)
0.006
[17]
LTA
6p21
rs909253
A/G
Intronic
51; 48
1.98 (1.02–3.8)
c
0.041
[20]
MGEA5
10q24
MGEA5-14
A/T
Intronic
271; 244
1.60 (0.52–4.86)
0.404
[21]
NOTCH2
1p11
rs10923931
G/T
Intronic
1027; 990
1.04 (0.82–1.32)d
0.731
[8]
NQO1
16q22
rs1800566
C/T
P/S
623; 993
0.98 (0.85–1.13)c
0.76
[18]
NRF2
2q31
rs2364723
C/G
Intronic
625; 992
0.91 (0.79–1.05)c
0.18
[18]
NRF2
2q31
rs6721961
C/A
Promoter
623; 989
0.89 (0.74–1.06)c
0.18
[8]
NXPH1
7p22
rs757705
A/G
Intronic
868; 504
1.25 (1.05–1.48)
k
0.01
[8]
PPARG
3p25
rs1801282
C/G
P/A
719; 746
1.00 (0.81–1.24)c,f
1.00
[12]
rs1801282
C/G
P/A
1027; 990
1.10 (0.90–1.34)d
0.342
[8]
rs17793693
A/C
Intronic
519; 547
1.09 (0.91–1.31)c
0.329
[10]
RALGPS2
1q25
rs2773080
A/G
Intronic
868; 504
0.90 (0.74–1.10)e
0.315
[8]
RORA
15q22
rs7164773
C/T
Intronic
868; 504
1.08 (0.91–1.28)e
0.357
[8]
SIRT1
10q21
rs3758391
C/T
Upstream
519; 547
1.29 (1.08–1.54)
c
0.004
[10]
SLC30A4
8q24
rs13266634
C/T
R/W
455; 234
1.01 (0.76–1.33)
0.92
[17]
rs13266634
C/T
R/W
1027; 990
1.22 (1.05–1.41)
d
0.009
[8]
TCF7L2
10q25
rs7903146
C/T
Intronic
868; 504
1.04 (0.84–1.28)e,l
0.735
[8]
rs7903146
C/T
Intronic
200; 200
1.84 (1.05–3.20)
c
,
m
0.04
[12]
rs7903146
C/T
Intronic
519; 547
1.48 (1.18–1.86)
c
0.0007
[10]
rs7903146
C/T
Intronic
283; 271
1.25 (0.92–1.70)
0.16
[22]
rs12255372
G/T
Intronic
200; 200
1.83 (1.21–2.76)
c
,
m
0.006
[12]
rs12255372
G/T
Intronic
281; 268
1.78 (1.11–2.88)
0.017
[22]
rs12255372
G/T
Intronic
519; 547
1.37 (1.06–1.76)
c
0.014
[10]
DG10S478
STR CACA
Intronic
282; 274
1.62 (1.02–2.57)
0.041
[22]
TLR2
4q32
rs5743708
G/A
R/Q
321; 538
0.41 (0.04–3.7)
0.40
[23]
TLR4
9q33
rs4986790
A/G
D/G
321; 538
1.39 (0.42–4.56)
0.58
[23]
rs4986791
C/T
T/I
321; 538
1.01 (0.32–3.18)
0.98
[23]
TNF-α
6p21
rs1800629
-308G/A
Upstream
51; 48
0.76 (0.31–1.85)c,n
0.55
[20]
rs1800629
-308G/A
Upstream
95; 87
4.66 (1.73–12.5)
c
0.001
[24]
rs1800629
-308G/A
Upstream
259; 645
1.25 (0.83–1.87)
0.29
[25]
rs361525
-238G/A
Upstream
259; 645
1.57(1.07–2.29)
0.018
[25]
TSPAN8/LGR5
12q14–q21
rs7961581
C/T
Intergenic
868; 504
0.93 (0.73–1.17)e
0.516
[8]
TXNIP
1q21
rs7211
C/T
3′ UTR
623; 969
0.97 (0.82–1.14)
0.67
[18]
UBQLNL
11p15
rs979752
C/T
Upstream
868; 504
1.04 (0.84–1.30)e
0.70
[8]
Chrom: chromosome. Risk alleles are marked in bold.na; nb. Sample for cases and controls, respectively. cConventional OR (unadjusted) was assessed by us from allele or genotype frequencies reported. dLargest n was registered. eTest without ancestry correction was considered. fCombined datasets were registered. gRisk was only observed in nonobese T2D patients (OR = 1.25; p=0.009). hOnly Genotypes of T2D patients and healthy controls were used in our analysis. iAssessment derived from the sum of T2D patients (obese and nonobese). jThe authors reported a protector effect for the A allele (OR = 0.65; p < 0.001), but in our estimation we took as reference the A allele, since it is the most common. kSignificant analysis with ancestry correction was taken. lAssociation was only found in early-onset T2D (OR = 1.39; p=0.024). mJust the population of Guerrero was recorded due to possible overlapping of the patients from the Mexico City with [10]. nThe G allele was assessed as risk by the authors; but in our analysis we took the A allele, the same as that in previous studies.Table 2
Analysis of SNPs studied by two or more groups in Mexican mestizos.
Gene
dbSNP loc
Cases(allele)
Controls(allele)
Risk allele frequency(%)
OR (95% CI)
p
∗ value
Reference
Cases
Controls
CAPN10
rs3792267
1086
928
29.5
28.7
1.06 (0.87–1.29)
0.56
[11–13]
CAPN10
rs3842570
772
656
61.7
62.5
0.96 (0.78–1.20)
0.74
[11, 13, 14]
CAPN10
rs5030952
686
530
19.0
18.3
1.04 (0.78–1.40)
0.78
[11, 13]
CDKAL1
rs7754840
3092
3074
31.4
29.1
1.12 (1.00–1.25)
0.044
[8, 10]
HHEX
rs1111875
2974
2448
62.8
61.7
1.05 (0.94–1.17)
0.43
[8, 17]
IRS1
rs1801278
2326
2380
6.6
2.8
2.45 (1.83–3.28)
<0.0001
[12, 19]
PPARG
rs1801282
3492
3472
87.3
86.7
1.05 (0.91–1.21)
0.51
[8, 12]
SLC30A4
rs13266634
2964
2448
76.3
73.0
1.19 (1.05–1.35)
0.005
[8, 17]
TCF7L2
rs7903146
3740
3042
17.8
14.1
1.32 (1.16–1.50)
<0.0001
[8, 12, 22]
TCF7L2
rs12255372
2476
2586
18.3
11.6
1.40 (1.19–1.65)
<0.0001
[12, 22]
TNF-α
rs1800629
810
1560
11.5
6.2
1.96 (1.45–2.64)
<0.0001
[20, 24, 25]
Y
a
t
e
s
∗’ correction chi-square test.


## 4. Discussion

This review about genetics of T2D in Mexican mestizo subjects shows that 26 polymorphisms distributed in 21 genes are associated with this disease, so T2D has a high heterogeneity in our population, the same as that in other ethnic groups. Therefore, in some individuals alleles of certain genes are involved, while in others subjects are implicated variants of different genes. A previous conclusion that T2D in Mexican mestizos is genetically homogeneous was based on an analysis of three genetic markers [26] and here appears untenable. Though the Mexican mestizo population has a European genetic ancestry near 30% [27], not all the alleles conferring diabetes risk in Europeans are associated with T2D in our population [8]. These variations could be related to genetic background, differences in clinical classifications, sample size, selection and analysis criteria, and environmental factors such as obesity, lifestyle, and diet. On the other hand, researches in several ethnic groups have shown association of T2D with genes not yet analyzed in Mexican population [5, 6, 28–32]. It would be important to carry out the analysis of such genes to determine whether these variants are also associated with T2D in Mexican patients and increase the knowledge about the genetic epidemiology of this disorder in our country.Regarding Mexican studies, an increased risk was detected when analysis was performed adjusting covariates. For instance, Cruz et al. observed an additive effect in the T2D risk when they considered variables such as age, education, sex, body mass index, and ancestry [10]. Gamboa-Meléndez et al. reported association with T2D for the polymorphisms rs7923837(HHEX), rs4402960(IGF2BP2), and rs2237892(KCNQ1) only when ancestry was adjusted [8]. For the polymorphisms rs864745(JAZF1) and rs757705(NXPH1), the analysis stratified by ancestry did not show significant differences, whereas an association was observed in the comparison without such an adjustment. In addition, they found association for rs7903146(TCF7L2) and rs7754840(CDKAL1) just in early-onset T2D [OR = 1.39 (1.04–1.85), p=0.024] and in nonobese T2D patients [OR = 1.25 (1.06–1.49), p=0.009], respectively. Another study found a lower OR when the analysis was adjusted by sex, body mass index, and family history of T2D for three polymorphisms ofIRS1 in a dominant model [19].The reported association of rs3842570(CAPN10) [14], rs909253(LTA) [20], and rs1800629(TNF-α) [24] with T2D should be interpreted with caution given the small sample sizes and poor statistical power. With respect to the rs1345365 polymorphism(ELMO1), the authors reported a protector effect for the A allele [OR = 0.65 (0.55–0.78),p < 0.001] [16]. But in our analysis we took as reference the A allele, as it is the most common; thus, the G allele showed association with T2D [OR = 1.37 (1.02 to 1.84), p=0.035].Since T2D is a complex disorder and several genes are implicated in its etiology and evolution, the identification of risk alleles could be useful, because if the involved genes and their function are known, it is more probable to achieve prevention, treatment, prognosis, and/or cure of the disease. Complications could also be prevented or treated better [29, 33]. However, published studies demonstrate that genetic screening for the prediction of T2D in high risk subjects is currently of little value in clinical practice. Actually, genetic risks are difficult to calculate because several alleles could contribute to an additive effect to T2D susceptibility [34], not to mention the diverse environmental factors involved. Although some of these genes are implicated in the glucose and fat metabolism, β-cell function, and sensitivity and secretion of insulin [29, 35], how some of their variants increase the T2D risk remains to be elucidated [29]. Anyway, it is fundamental to analyze the genetic epidemiology of this disease in each population because of the underlying differences in genetic background and lifestyle among ethnic groups. So, it is possible that polymorphisms associated with T2D in some races do not show association in others. Genome-wide association studies will ultimately precise the genetic landscape.



---

*Source: 3937893-2017-05-18.xml*