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


ABSTRACT: Background- Variation in LDL-cholesterol (LDL-C) among individuals is a complex genetic trait involving multiple genes and gene-environment interactions.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%Deltaexon13/total HMGCR mRNA, P=0.02). Further, the alternative splice variant could not restore HMGCR activity when expressed in HMGCR deficient UT-2 cells.We identified variants in HMGCR that are associated with LDL-C across populations and affect alternative splicing of HMGCR exon13.

SUBMITTER: Burkhardt R 

PROVIDER: S-EPMC2764366 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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

Burkhardt Ralph R   Kenny Eimear E EE   Lowe Jennifer K JK   Birkeland Andrew A   Josowitz Rebecca R   Noel Martha M   Salit Jacqueline J   Maller Julian B JB   Pe'er Itsik I   Daly Mark J MJ   Altshuler David D   Stoffel Markus M   Friedman Jeffrey M JM   Breslow Jan L JL  

Arteriosclerosis, thrombosis, and vascular biology 20080918 11


<h4>Unlabelled</h4>Background- Variation in LDL-cholesterol (LDL-C) among individuals is a complex genetic trait involving multiple genes and gene-environment interactions.<h4>Methods and results</h4>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 r  ...[more]

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