on September 18, 2008
Published online before print September 18, 2008, doi: 10.1161/ATVBAHA.108.172288
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Submitted on June 17, 2008
Accepted on August 1, 2008
Common SNPs in HMGCR in Micronesians and Whites Associated With LDL-Cholesterol Levels Affect Alternative Splicing of Exon13
Ralph Burkhardt ;
From the Laboratory of Biochemical Genetics and Metabolism (R.B., E.E.K., J.K.L., A.B., R.J., M.N., J.L.B.), the Laboratory of Molecular Genetics (J.S., J.M.F.), Howard Hughes Medical Institute (J.M.F.), The Rockefeller University, New York; the Broad Institute of Harvard and MIT (J.K.L., J.B.M., M.J.D., D.A.), Cambridge, Mass; the Department of Computer Science (I.P.), Columbia University, New York; the Center for Human Genetics Research (J.B.M., M.J.D.) and the Department of Molecular Biology (D.A.J., K.L.), Massachusetts General Hospital, Boston; the Department of Medicine (M.J.D., D.A.) and the Department of Genetics (D.A.), Harvard Medical School, Boston, Mass; and the Institute of Molecular Systems Biology (M.S.), ETH Zurich, Switzerland.
* To whom correspondence should be addressed. E-mail: breslow{at}rockefeller.edu.
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%
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.
Key words: HMG-CoA reductase • SNP • genome-wide association study • LDL-C • alternative splicing
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