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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.

Original publication

DOI

10.1371/journal.pgen.1000798

Type

Journal article

Journal

PLoS genetics

Publication Date

08/01/2010

Volume

6

Addresses

Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden. wilmar.igl@genpat.uu.se

Keywords

EUROSPAN Consortium, Humans, Cholesterol, Haptoglobins, Diet, Cohort Studies, Cross-Sectional Studies, Pedigree, Motor Activity, Life Style, Polymorphism, Single Nucleotide, Models, Genetic, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, European Continental Ancestry Group, Sweden, Female, Male, Glucose Transporter Type 2, Genome-Wide Association Study, Young Adult