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Meta-Analysis
. 2011 Apr;4(2):145-55.
doi: 10.1161/CIRCGENETICS.110.957563. Epub 2011 Feb 8.

Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol

Affiliations
Meta-Analysis

Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol

Andrew C Edmondson et al. Circ Cardiovasc Genet. 2011 Apr.

Abstract

Background: Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs.

Methods and results: Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664) and provide evidence that suggests an association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants.

Conclusions: Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.

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Figures

Figure 1
Figure 1
HDL-C Regional Association plots. P-values from SNPs in loci with multiple, independent association signals (A) CETP, (B) LPL, (C) LIPG, (D) APOA1/A4/A5/C3, (E) ABCA1 are plotted with linkage disequilibrium plots, which have been enlarged to show the region between the asterisks.
Figure 1
Figure 1
HDL-C Regional Association plots. P-values from SNPs in loci with multiple, independent association signals (A) CETP, (B) LPL, (C) LIPG, (D) APOA1/A4/A5/C3, (E) ABCA1 are plotted with linkage disequilibrium plots, which have been enlarged to show the region between the asterisks.
Figure 1
Figure 1
HDL-C Regional Association plots. P-values from SNPs in loci with multiple, independent association signals (A) CETP, (B) LPL, (C) LIPG, (D) APOA1/A4/A5/C3, (E) ABCA1 are plotted with linkage disequilibrium plots, which have been enlarged to show the region between the asterisks.
Figure 1
Figure 1
HDL-C Regional Association plots. P-values from SNPs in loci with multiple, independent association signals (A) CETP, (B) LPL, (C) LIPG, (D) APOA1/A4/A5/C3, (E) ABCA1 are plotted with linkage disequilibrium plots, which have been enlarged to show the region between the asterisks.
Figure 1
Figure 1
HDL-C Regional Association plots. P-values from SNPs in loci with multiple, independent association signals (A) CETP, (B) LPL, (C) LIPG, (D) APOA1/A4/A5/C3, (E) ABCA1 are plotted with linkage disequilibrium plots, which have been enlarged to show the region between the asterisks.

References

    1. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The framingham study. Am J Med. 1977;62:707–714. - PubMed
    1. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, Byun J, Vuletic S, Kassim S, Singh P, Chea H, Knopp RH, Brunzell J, Geary R, Chait A, Zhao XQ, Elkon K, Marcovina S, Ridker P, Oram JF, Heinecke JW. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of hdl. J Clin Invest. 2007;117:746–756. - PMC - PubMed
    1. Cuchel M, Rader DJ. Macrophage reverse cholesterol transport: Key to the regression of atherosclerosis? Circulation. 2006;113:2548–2555. - PubMed
    1. Rader DJ. Molecular regulation of hdl metabolism and function: Implications for novel therapies. J Clin Invest. 2006;116:3090–3100. - PMC - PubMed
    1. Heller DA, de Faire U, Pedersen NL, Dahlen G, McClearn GE. Genetic and environmental influences on serum lipid levels in twins. N Engl J Med. 1993;328:1150–1156. - PubMed

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