Common SNPs in HMGCR in Micronesians and Whites Associated With LDL-Cholesterol Levels Affect Alternative Splicing of Exon13

被引：109

作者：

Burkhardt, Ralph ^{[11
]}

Kenny, Eimear E. ^{[11
]}

Lowe, Jennifer K. ^{[3
,4
,7
,11
]}

Birkeland, Andrew ^{[11
]}

Josowitz, Rebecca ^{[11
]}

Noel, Martha ^{[11
]}

Salit, Jacqueline

Maller, Julian B. ^{[3
,4
,6
]}

Pe'er, Itsik ^{[5
]}

Daly, Mark J. ^{[3
,4
,6
,8
]}

Altshuler, David ^{[3
,4
,7
,8
,9
]}

Stoffel, Markus ^{[10
]}

Friedman, Jeffrey M. ^{[2
]}

Breslow, Jan L. ^{[1
,11
]}

机构：

[1] Rockefeller Univ, Lab Biochem Genet, New York, NY 10065 USA

[2] Rockefeller Univ, Howard Hughes Med Inst, Mol Genet Lab, New York, NY 10065 USA

[3] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA

[4] MIT, Cambridge, MA 02139 USA

[5] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA

[6] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[7] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[8] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[9] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[10] ETH, Inst Mol Syst Biol, Zurich, Switzerland

[11] Rockefeller Univ, Biochem Genet & Metab Lab, New York, NY 10065 USA

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2008年 / 28卷 / 11期

关键词：

HMG-CoA reductase; SNP; genome-wide association study; LDL-C; alternative splicing;

D O I：

10.1161/ATVBAHA.108.172288

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-Variation in LDL-cholesterol (LDL-C) among individuals is a complex genetic trait involving multiple genes and gene-environment interactions. Methods and Results-In a genome-wide association study (GWAS) to identify genetic variants influencing LDL-C in an isolated population from Kosrae, we observed associations for SNPs in the gene encoding 3hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR). Three of these SNPs (rs7703051, rs12654264, and rs3846663) met the statistical threshold of genome-wide significance when combined with data from the Diabetes Genetics Initiative GWAS. We followed up the association results and identified a functional SNP in intron13 (rs3846662), which was in linkage disequilibrium with the SNPs of genome-wide significance and affected alternative splicing of HMGCR mRNA. In vitro studies in human lymphoblastoid cells demonstrated that homozygosity for the rs3846662 minor allele was associated with up to 2.2-fold lower expression of alternatively spliced HMGCR mRNA lacking exon13, and minigene transfection assays confirmed that allele status at rs3846662 directly modulated alternative splicing of HMGCR exon13 (42.9 +/- 3.9 versus 63.7 +/- 1.0%Delta exon13/total HMGCR mRNA, P = 0.02). Further, the alternative splice variant could not restore HMGCR activity when expressed in HMGCR deficient UT-2 cells. Conclusion-We identified variants in HMGCR that are associated with LDL-C across populations and affect alternative splicing of HMGCR exon13. (Arterioscler Thromb Vasc Biol. 2008; 28: 2078-2084)

引用

页码：2078 / U332

页数：18

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