Abstract P190: Genome-wide Association Study Suggests that Inflammation and Insulin Regulation Pathways May Mediate Lipoprotein Diameter Response to Fenofibrate
Authors: Wood Alexis C , Aslibekyan Stella , Strake Robert J , Borecki Ingrid B , Tiwari Hemant K , Tsai Michael Y , Hopkins Paul N , Ordovas Jose M , Kabagambe Edmond K , Arnett Donna K 
Published: July 2021

Shifts in lipoprotein diameter occur in insulin resistant (IR) patients - a known risk factor for cardiovascular disease. Fenofibrate modulates lipoprotein markers in a manner which is expected to reduce the risk of adverse cardiovascular events. However inter-individual variability in response to fenofibrate is very high. We aimed to examine phenotype-variant associations with shifts in lipoprotein diameter, for each of the three fractions of lipoprotein, in response to a three-week fenofibrate trial. Participants formed the general population sample from that Genetics of Lipid Lowering Drugs and Diet Network (n=817; mean age of 48.8 ± 16.2 y). Very-low, low- and high- density lipoprotein diameters were measured using NMR spectroscopy before and after a 3-week fenofibrate treatment (160mg/day). Lipoprotein diameter change, for each fraction, was calculated using growth curve models which modeled compliance with the fenofibrate protocol. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and lipoprotein diameter change were assessed using mixed linear models, adjusted for age, sex, study center, and family. A Bonferroni correction for multiple testing was used, with genome wide levels of significance set at
P
<1.97*10
-08
. Given power problems inherent in using change scores, suggestive levels of significance were set at
P
<1.97 * 10
-06
where there were more than five hits at this level within a 500kb region. The
AHCLY2
(
P
<3.95*10
-08
) gene was significantly associated with very-low density lipoprotein diameter. 14 genes reached suggestive levels of significance (
Table 1
). We conclude that genes previously associated with inflammation (
LPAR1
,
GRP110
) and insulin (
PION
,
EIF2AK3
,
CHRM3
,
WNT
) may mediate lipoprotein diameter response to fenofibrate. Upon replication in clinical populations, this may help understand the co-occurrence of IR, inflammation and cardiovascular disease as well the mechanisms of action and therapeutic potential of fenofibrate's role in patients with IR.

Table 1

Significant, and suggestive genotype-phenotype associations from a genome-wide study investigating genetic associations with VLDL, LDL and HDL diameter changes in response to fenofibrate

Gene

Response phenotype
1

P-value
2

Previous associations
3

AHCLY2

VLDL

3.95*10
-09

Produces an enzyme necessary for methylation

DOCK4

VLDL

1.39*10
-07

-

PPARG

HDL

2.87*10
-07

Increases expression of ABCA1; target of thiazolidinediones used to treat insulin resistance

ACCSL

HDL

5.18*10
-07

-

TFAP2A

HDL

5.26*10
-07

cardiomyopathy

PPTC7

HDL

6.40*10
-07

-

NSUN3

HDL

6.45*10
-07

-

RPLP1

HDL

6.47*10
-07

-

ORK2

HDL

9.10*10
-07

Olfactory receptor G-protein coupled gene

LPAR1

HDL

9.10*10
-07

inflammation, adipogenesis

GPR110

VLDL

2.97*10
-06

G-protein coupled gene, inflammation

EIF2AK3

VLDL

7.02*10
-06

insulin secretion, type 2 diabetes

CHRM3

HDL

3.63*10
-06

insulin secretion, type 2 diabetes

PLD1

VLDL

6.75*10
-06

insulin secretion and lipid droplet formation

TINK

VLDL

6.75*10
-06

wnt signaling, type 2 diabetes

Abbreviations: VLDL: very-low density lipoprotein; LDL: low-density lipoprotein, HDL: High density lipoprotein
1
Diameter change
2
Smallest p-value for a single phenotype-variant association within the gene
3
PubMed searches for the genes where within the gene single nucleotide polymorphisms were associated at (
P
<1.97 * 10
-06
).