Genome-wide Association with C-Reactive Protein Levels in CLHNS: Evidence for the CRP and HNF1A Loci and their Interaction with Exposure to a Pathogenic Environment

Abstract

Recent genome-wide association studies have related several genetic loci, including C-reactive protein (CRP), hepatocyte nuclear factor 1 homeobox (HNF1A), and genetic variations in the leptin receptor (LEPR), to circulating CRP levels in populations of European ancestry. The genetic effects in other populations and across varying levels of exposure to a pathogenic environment, an important environmental factor associated with CRP, remain to be determined. We tested 2,073,674 single-nucleotide polymorphisms (SNPs) for association with plasma CRP (limited to ≤10mg/L) in 1,709 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey. The strongest evidence of association was observed with variants at CRP (rs876537, P = 1.4 × 10(-9)) and HNF1A (rs7305618, P = 1.0 × 10(-8)). Among other previously reported CRP-associated loci, the apolipoprotein E ε4 haplotype was associated with decreased CRP level (P = 7.1 × 10(-4)), and modest association was observed with LEPR (rs1892534, P = 0.076), with direction of effects consistent with previous studies. The strongest signal at a locus not previously reported mapped to a gene desert region on chromosome 6q16.1 (rs1408282, P = 2.9 × 10(-6)). Finally, we observed nominal evidence of interaction with exposure to a pathogenic environment for top main effect SNPs at HNF1A (rs7305618, P = 0.031), LEPR (rs1892535, P = 0.030) and 6q16.1 (rs1408282, P = 0.046). Our findings demonstrate convincing evidence that genetic variants in CRP and HNF1A contribute to plasma CRP in Filipino women and provide the first evidence that exposure to a pathogenic environment may modify the genetic influence at the HNF1A, LEPR, and 6q16.1 loci on plasma CRP level.