Modeling of environmental effects in genome-wide association studies identifies SLC2A2 and HP as novel loci influencing serum cholesterol levels

Genome-wide association studies (gwas) have identified 38 larger genetic regions affecting classical blood lipid levels without adjusting for important environmental influences. we modeled diet and physical activity in a gwas in order to identify novel loci affecting total cholesterol,ldl cholesterol,hdl cholesterol,and triglyceride levels. the swedish (se) eurospan cohort (n se = 656) was screened for candidate genes and the non-swedish (ns) eurospan cohorts (nns = 3,282) were used for replication. in total,3 snps were associated in the swedish sample and were replicated in the non-swedish cohorts. while snp rs1532624 was a replication of the previously published association between cetp and hdl cholesterol,the other two were novel findings. for the latter snps,the p-value for association was substantially improved by inclusion of environmental covariates: snp rs5400 (p se,unadjusted = 3.6x10-5,pse,adjusted = 2.2x10-6,pns,unadjusted = 0.047) in the slc2a2 (glucose transporter type 2) and rs2000999 (pse,unadjusted = 1.1x10 -3,pse,adjusted = 3.8x10-4,p ns,unadjusted = 0.035) in the hp gene (haptoglobin-related protein precursor). both showed evidence of association with total cholesterol. these results demonstrate that inclusion of important environmental factors in the analysis model can reveal new genetic susceptibility loci. © 2010 igl et al.