Chapter 117S

Newly identified loci that influence plasma lipid concentrations include markers in and around the genes encoding lipoprotein lipase (LIPD), hepatic lipase (LIPC), and endothelial lipase (LIPG). These studies involved genome-wide scans of associations with low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), and triglyceride levels in population samples totaling more than 20,000 individuals. 1,2 Highly significant associations with HDLC were observed, with markers at 11 loci related to lipid metabolism. These polymorphisms were tested subsequently for association with the risk for coronary artery disease (CAD). In summary, markers at the CETP, LIPD, LIPC, and LIPG, LCAT, GALNT2, and ABCA1 loci were observed to be associated with HDLC levels. The impact of these common polymorphisms on HDLC levels ranged from approximately 1–4 mg/dl per allele. Markers at or near the LDLR, APOB, NCAN, SORT1, and APOE loci were associated with LDLC levels. The impact of these common polymorphisms on LDLC levels ranged from approximately 2–9 mg/dl per allele. Markers at or near the LPL, LIPD , APOA1-APOC3-APOA4-APOA5, NCAN, GCKR, ANGPTL3, TRIB1, CILP2, and GALNT2 loci were associated with triglyceride levels. The impact of these common polymorphisms on triglyceride levels ranged from approximately 1–26 mg/dl per allele. Multiple regression models indicated that only about 5–8 percent of the variation in the preceding three lipid parameters was accounted for by the associated alleles. Therefore, much of the heritability of these traits remains unknown. Uncommon alleles with relatively high impact and more common alleles with very low impact may be other contributing gene variants. Epigenetic variation also may have an impact on common variations in phenotype.

The alleles associated with lipid concentrations were tested subsequently for association with CAD in case-control studies. Interestingly, the 11 independent variants that were associated with elevated LDLC levels were more common among individuals with CAD. As expected from the small impact of alleles on LDLC levels, the risk estimates for CAD were quite small (~1–1.3 relative risk per allele). No associations of SNPs associated with HDLC and triglyceride were observed to be significantly associated with CAD in these studies. This lack of association may be due in part to the findings that elevated HDLC levels may have either an atherogenic or an antiatheogenic effect because high HDLC levels may result from a block of reverse cholesterol transport and may be associated with small, dense LDL. For example, a LIPC promoter polymorphism that is associated with HDL2C (antiatherogenic) also may have an atherogenic effect because it affects LDL density.4 Interestingly, some of the alleles that were strongly associated with LDLC were not significantly associated with increased risk for CAD, and other alleles that were strongly associated with CAD were not associated with lipid concentrations.1

Consistent with the preceding association of markers at the adipokine angiopoietin-like protein 3 (ANGPTL3) with triglyceride levels in the genome-wide studies,1 a subsequent population based resequencing ...

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