Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13

Ralph Burkhardt, Eimear E. Kenny, Jennifer K. Lowe, Andrew Birkeland, Rebecca Josowitz, Martha Noel, Jacqueline Salit, Julian B. Maller, Itsik Pe'er, Mark J. Daly, David Altshuler, Markus Stoffel, Jeffrey M. Friedman, Jan L. Breslow

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


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%Δ13/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.

Original languageEnglish (US)
Pages (from-to)2078-2084
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number11
StatePublished - Nov 1 2008
Externally publishedYes


  • Alternative splicing
  • Genome-wide association study
  • HMG-CoA reductase
  • LDL-C
  • SNP

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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