Analyses of longitudinal effects of gene-environment interactions on plasma C-reactive protein levels: the Hallym Aging Study

High C-reactive protein (CRP) level (above 3 mg/L), an inflammatory biomarker, is a well-known risk factor for cardiovascular disease. We investigated the longitudinal effects of interaction between genetic variants of seven candidate loci (i.e., IL6R, CRP, GCKR, IL6, CYP17A1, HNF1A, and APOE) and eight non-genetic factors (i.e., body mass index (BMI), total cholesterol to high density lipoprotein cholesterol ratio (T/HDL), systolic blood pressure, diastolic blood pressure (DBP), current smoking, alcohol consumption, regular exercise, and sleeping hours) on plasma hsCRP levels in a community-based cohort composed of 1,051 elderly Korean participants with a 6-year follow up. We applied a recently developed nonparametric approach, Survival Dimensionality Reduction (SDR) to evaluate gene-environment interactions using follow up data, and compared the results to those of conventional statistical approaches, Cox proportional hazard (CPH) regression model and log-rank test. Four gene variants significantly interacted with three non-genetic factors: SNPs rs2293571 (GCKR), rs1004467 (CYP17A1) and high DBP (HR = 3.22 and 2.95, P _G×E = 0.013 and 0.017, respectively); rs2464196 (HNF1A) and two non-genetic factors, regular exercise (HR = 3.78, P _G×E = 0.043) and high T/HDL (HR = 4.54, P _G×E = 0.042); and rs439401 (APOE) and regular exercise (HR = 3.01, P _G×E = 0.049). The interaction between the rs2464196 and T/HDL was consistently observed in both CPH model and SDR model (Accuracy = 0.86, P = 0.011). Investigating the effects of gene-environment interactions on baseline plasma hsCRP concentrations will provide clues to identify the pathway involved in increasing hsCRP level and the risks of related diseases.