3 research outputs found
Large-scale gene-centric analysis identifies novel variants for coronary artery disease.
Coronary artery disease (CAD) has a significant genetic contribution that is
incompletely characterized. To complement genome-wide association (GWA) studies,
we conducted a large and systematic candidate gene study of CAD susceptibility,
including analysis of many uncommon and functional variants. We examined 49,094
genetic variants in 3c2,100 genes of cardiovascular relevance, using a customised
gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733
controls of European descent; 4,394 cases and 4,259 controls of South Asian
origin). We attempted to replicate putative novel associations in an additional
17,121 CAD cases and 40,473 controls. Potential mechanisms through which the
novel variants could affect CAD risk were explored through association tests with
vascular risk factors and gene expression. We confirmed associations of several
previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19);
1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2,
ZC3HC1, CYP17A1:p<5
710(-7)). However, we found essentially null results for most
previously suggested CAD candidate genes. In our replication study of 24
promising common variants, we identified novel associations of variants in or
near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk
with each of the novel variants ranging from 1.06-1.09. Associations with
variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data
or effects on lipid levels. Apart from the previously reported variants in LPA,
none of the other 3c4,500 low frequency and functional variants showed a strong
effect. Associations in South Asians did not differ appreciably from those in
Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27
respectively; P for heterogeneity\u200a=\u200a0.003). This large-scale gene-centric
analysis has identified several novel genes for CAD that relate to diverse
biochemical and cellular functions and clarified the literature with regard to
many previously suggested genes