Epistasis between SNPs in genes involved in lipoprotein metabolism influences high- and low-density lipoprotein cholesterol levels.

Abstract

Although genome-wide association (GWA)

studies have provided valuable insights into the genetic

architecture of human disease, they have elucidated relatively

little of the heritability of complex traits. A significant

part of the missing heritability might be explained by

rare combinations of common SNPs. We hypothesized that

epistasis among 15 genes (148 SNPs) involved in lipoprotein

metabolism would influence HDL-cholesterol

(HDL-C) and LDL-cholesterol (LDL-C) levels. Using

SNPwinter software with the various epistatic models, we

identified 58 association signals with HDL-C levels for

SNPs in eleven genes and 118 associations with LDL-C for

SNPs in fourteen genes. These associations were discovered

in the urban Ansan cohort (n = 4,102) and replicated

in a rural cohort (n = 3,434), the Ansung. We found replicated

associations with new genes (SOAT1, APOB,

HMGCR, and FDFT1 for HDL-C, and SOAT1, FDFT1,

LPL, SQLE, ABCA1, LRP1, SCARB1, and PLTP for LDLC),

in addition to those (CETP, LIPC, LPL, ABCA1, PLTP,

SCARB1, and LRP1 for HDL-C, and CETP, LIPC, LDLR,

APOB, CYP7A1, and HMGCR for LDL-C) identified by

GWA studies, through investigating pairwise interactions

between candidate genes of biological and clinical importance.

Interestingly, we found that some genes were more

likely to be involved in epistatic interactions (ABCA1 and

LIPC for HDL-C, and ABCA1, SCARB1, and LIPC for

LDL-C).