PuSH - Publication Server of Helmholtz Zentrum München: Modeling of environmental effects in genome-wide association studies identifies <em>SLC2A2 </em>and <em>HP</em> as novel loci influencing serum cholesterol levels.

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Igl, W.* ; Johansson, A.* ; Wilson, J.F.* ; Wild, S.H.* ; Polasek, O.* ; Hayward, C.* ; Vitart, V.* ; Hastie, N.* ; Rudan, P.* ; Gnewuch, C.* ; Schmitz, G.* ; Meitinger, T. ; Pramstaller, P.P.* ; Hicks, A.A.* ; Oostra, B.A.* ; van Duijn, C.M.* ; Rudan, I.* ; Wright, A.* ; Campbell, H.* ; Gyllensten, U.*

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

PLoS Genet. 6:e1000798 (2010)

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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 (N(NS) = 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) = 3.6 x 10(-5), p(SE,adjusted) = 2.2 x 10(-6), p(NS,unadjusted) = 0.047) in the SLC2A2 (Glucose transporter type 2) and rs2000999 (p(SE,unadjusted) = 1.1 x 10(-3), p(SE,adjusted) = 3.8 x 10(-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.

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