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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 × 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 × 10−4) and related to an effect on low-density lipoprotein (LDL) cholesterol ( P = 8.56 × 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. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either. [ABSTRACT FROM AUTHOR]

Linkage studies of complex diseases have so far had limited success in producing significant and replicable results, in part owing to genetic heterogeneity. We recently reported the results of a large genome-wide linkage scan for coronary artery disease (CAD) based on 1933 families. The greatest evidence for linkage was to a region of chromosome 2, with a logarithm of odds (LOD) score of 1.86, based on the non-parametric SALL statistic, which did not reach genome-wide significance (P>0.3). Inclusion of a covariate in linkage analysis can be a powerful method of accounting for disease heterogeneity. As CAD is a heterogeneous disease, we carried out a linkage analysis of chromosome 2 incorporating covariates. Increased evidence for linkage was found when hypercholesterolemia was considered (LOD score including covariate of 4.4) reaching genome-wide significance as assessed by simulation (P=0.04). Results showed that the original evidence for linkage was largely attributable to the subset of 108 non-hypercholesterolemic affected sibling pairs. In separate linkage analyses of subsets of hypercholesterolemic and non-hypercholesterolemic sibling pairs, the maximum LOD scores were 1.09 in the former group and 3.74 in the latter. This result illustrates the potential to increase the power of linkage analysis in the presence of heterogeneity by inclusion of covariates. This linked locus on chromosome 2 should now be investigated further to identify the gene(s) influencing risk of CAD in subjects with a normal level of total cholesterol. Candidate genes include the interleukin 1 cluster and two potential regulators of high-density lipoprotein cholesterol level, PLA2R1 and OSBPL6.European Journal of Human Genetics (2007) 15, 313–319. doi:10.1038/sj.ejhg.5201752; published online 6 December 2006 [ABSTRACT FROM AUTHOR]