title: The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol.
abstract: Through genome-wide association studies, we have recently identified seven novel loci that confer a substantial increase in risk for coronary artery disease (CAD). Elucidating the mechanisms by which these loci affect CAD risk could have important clinical utility. Here, we investigated whether these loci act through mechanisms involving traditional cardiovascular risk factors. We genotyped 2,037 adult individuals from 520 nuclear families characterised for body mass index, waist-hip ratio, 24-h ambulatory blood pressure, total cholesterol, high-density lipoprotein cholesterol and glucose for the lead single nucleotide polymorphisms (SNPs) in the seven CAD-associated loci. SNP rs599839, representing the locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1p13.3, showed a strong association with total cholesterol. The CAD-associated risk allele A of rs599839 (allele frequency 0.78) was associated with a 0.17-mmol/l (95% CI 0.10 to 0.24 mmol/l) higher serum cholesterol level per allele copy (P = 3.84 x 10(-6)). The association of the A allele with higher total cholesterol was confirmed in an independent cohort (n = 847) of healthy adults (P = 1.0 x 10(-4)) and related to an effect on low-density lipoprotein (LDL) cholesterol (P = 8.56 x 10(-5)). An association of rs599839 with LDL cholesterol was also shown in 1,090 cases with myocardial infarction (P = 0.0026). None of the other variants showed a strong association with the measured cardiovascular risk factors, suggesting that these loci act through other mechanisms. However, the novel CAD-associated locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1 probably enhances CAD risk through an effect on plasma LDL cholesterol. The findings support further investigation of the role of these genes in cholesterol metabolism and coronary risk.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK. njs@le.ac.uk
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Anika
authors.initials: A
authors.lastname: Götz
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.forename: Patrick
authors.initials: P
authors.lastname: Linsel-Nitschke
authors.forename: Cother
authors.initials: C
authors.lastname: Hajat
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Klaus
authors.initials: K
authors.lastname: Stark
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.forename: Paul R
authors.initials: PR
authors.lastname: Burton
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D015820:Cadherins / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009679:Nuclear Family; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D044465:White People
chemical_list: D001786:Blood Glucose; C498477:CELSR2 protein, human; D015820:Cadherins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C485740:PSRC1 protein, human; D010750:Phosphoproteins; D002784:Cholesterol