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 (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.
Igl
Wilmar
W
Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden. wilmar.igl@genpat.uu.se
Johansson
Asa
A
Wilson
James F
JF
Wild
Sarah H
SH
Polasek
Ozren
O
Hayward
Caroline
C
Vitart
Veronique
V
Hastie
Nicholas
N
Rudan
Pavao
P
Gnewuch
Carsten
C
Schmitz
Gerd
G
Meitinger
Thomas
T
Pramstaller
Peter P
PP
Hicks
Andrew A
AA
Oostra
Ben A
BA
van Duijn
Cornelia M
CM
Rudan
Igor
I
Wright
Alan
A
Campbell
Harry
H
Gyllensten
Ulf
U
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002784:Cholesterol / Q000097:blood*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004032:Diet; D005260:Female; D055106:Genome-Wide Association Study; D051273:Glucose Transporter Type 2 / Q000235:genetics*; D006242:Haptoglobins / Q000235:genetics*; D006801:Humans; D008019:Life Style; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009043:Motor Activity; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013548:Sweden; D044465:White People / Q000235:genetics; D055815:Young Adult
D051273:Glucose Transporter Type 2; C485359:HP protein, human; D006242:Haptoglobins; C495680:SLC2A2 protein, human; D002784:Cholesterol