Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.
Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.
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DOI：
10.1161/atvbaha.108.172288
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Breslow JL
中科院分区：
文献类型：
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作者：
Burkhardt R;Kenny EE;Lowe JK;Birkeland A;Josowitz R;Noel M;Salit J;Maller JB;Pe'er I;Daly MJ;Altshuler D;Stoffel M;Friedman JM;Breslow JL
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 HMG-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 vs. 63.7±1.0 %Δexon13/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.
