In:
Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 2 ( 2011-04), p. 145-155
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1942-325X
,
1942-3268
DOI:
10.1161/CIRCGENETICS.110.957563
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2011
detail.hit.zdb_id:
2927603-2
detail.hit.zdb_id:
2457085-0
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