Abstract
BackgroundGenome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) affecting high density lipoprotein (HDL) or low density lipoprotein (LDL) cholesterol levels; these SNPs may contribute to the genetic basis of vascular diseases.ResultsWe assessed the impact of 34 SNPs at 23 loci on dyslipidemia, key lipid sub-phenotypes, and severe carotid artery disease (CAAD) in a case-control cohort. The effects of these SNPs on HDL and LDL were consistent with those previously reported, and we provide unbiased estimates of the percent variance in HDL (3.9%) and LDL (3.3%) explained by genetic risk scores. We assessed the effects of these SNPs on HDL subfractions, apolipoprotein A-1, LDL buoyancy, apolipoprotein B, and lipoprotein (a) and found that rs646776 predicts apolipoprotein B level while rs2075650 predicts LDL buoyancy. Finally, we tested the role of these SNPs in conferring risk for ultrasonographically documented CAAD stenosis status. We found that two loci, chromosome 1p13.3 near CELSR2 and PSRC1 which contains rs646776, and 19q13.2 near TOMM40 and APOE which contains rs2075650, harbor risk alleles for CAAD.ConclusionOur analysis of 34 SNPs contributing to dyslipidemia at 23 loci suggests that genetic variation in the 1p13.3 region may increase risk of CAAD by increasing LDL particle number, whereas variation in the 19q13.2 region may increase CAAD risk by promoting formation of smaller, denser LDL particles.
Highlights
Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) affecting high density lipoprotein (HDL) or low density lipoprotein (LDL) cholesterol levels; these SNPs may contribute to the genetic basis of vascular diseases
Based on previous success in applying genetic risk scores for decreased HDL and increased LDL to the prediction of coronary artery disease[12] and the central role of these lipid fractions in evidence-based guidelines for coronary artery disease risk reduction[18], we investigated the role of SNPs affecting HDL and LDL in predicting risk for Carotid artery disease (CAAD)
Out of 34 SNPs tested, we identified 14 SNPs that showed nominally significant associations with HDL or LDL levels at a p-value of 0.05, corresponding to a false discovery rates (FDR) of 0.11 when corrected for multiple testing
Summary
Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) affecting high density lipoprotein (HDL) or low density lipoprotein (LDL) cholesterol levels; these SNPs may contribute to the genetic basis of vascular diseases. A number of large genome-wide association studies have revealed loci affecting total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides [11,12,13,14,15]. Because of their role in promoting dyslipidemia, these single nucleotide polymorphisms (SNPs) are strong candidates for contributing to genetic risk for atherosclerosis, and several studies have found significant impacts of these loci on coronary artery disease[11,12,16]. The impact of recently discovered dyslipidemia risk alleles on CAAD is as yet unknown
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