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
Recent genome-wide association (GWA) studies have related several genetic loci, including CRP, HNF1A and LEPR, to circulating C-reactive protein (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 SNPs for association with plasma CRP (limited to ≤ 10 mg/L) in 1,709 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). 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 APOE 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
