Adiposity significantly modifies genetic risk for dyslipidemia

Christopher B Cole,Majid Nikpay,Paulina Lau,Alexandre F.R Stewart,Robert W Davies,George A Wells,Robert Dent,Ruth Mcpherson

doi:10.1194/jlr.p052522

Christopher B Cole, Majid Nikpay + Show 6 more

Open Access

https://doi.org/10.1194/jlr.p052522

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Abstract

Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain <12% of variation in lipid traits. Adiposity is also an important determinant of plasma lipoproteins, particularly plasma TGs and HDL cholesterol (HDLc) concentrations. Thus, interactions between genes and clinical phenotypes may contribute to this unexplained heritability. We have applied a weighted genetic risk score (GRS) for both plasma TGs and HDLc in two large cohorts at the extremes of BMI. Both BMI and GRS were strongly associated with these lipid traits. A significant interaction between obese/lean status and GRS was noted for each of TG (PInteraction = 2.87 × 10−4) and HDLc (PInteraction = 1.05 × 10−3). These interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc. In contrast, the GRSLDL cholesterol × adiposity interaction was not significant. Sexual dimorphism was evident for the GRSHDL on HDLc in obese (PInteraction = 0.016) but not lean subjects. SNP by BMI interactions may provide biological insight into specific genetic associations and missing heritability.

Highlights

= 2.87 × 10؊4) and HDL cholesterol (HDLc) interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc
Family-based association studies indicate that 40% to 60% of variation in plasma TG and HDLc is genetically based [4, 5], the identified loci explain
For coronary artery disease controls (CAD-C) subjects on lipid modifying medication, written documentation of pretreatment plasma lipids was obtained from the primary care physician and used for these analyses

Summary

Introduction

We have applied a weighted genetic risk score (GRS) for both plasma TGs and HDLc in two large cohorts at the extremes of BMI. Both BMI and GRS were strongly associated with these lipid traits. A significant interaction between obese/lean status and GRS was noted for each of = 2.87 × 10؊4) and HDLc interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc. In contrast, the GRSLDL cholesterol × adiposity interaction was not significant. SNP by BMI interactions may provide biological insight into specific genetic associations and missing heritability.—Cole, C. Environmental and clinical factors including BMI, physical activity, and alcohol intake are important determinants of plasma TG and HDLc [6]

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