Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 2078-2084 |
| Number of pages | 7 |
| Journal | Arteriosclerosis, Thrombosis, and Vascular Biology |
| Volume | 28 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2008 |
| Externally published | Yes |
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Keywords
- Alternative splicing
- Genome-wide association study
- HMG-CoA reductase
- LDL-C
- SNP
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
Cite this
Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13. / Burkhardt, Ralph; Kenny, Eimear E.; Lowe, Jennifer K.; Birkeland, Andrew; Josowitz, Rebecca; Noel, Martha; Salit, Jacqueline; Maller, Julian B.; Pe'er, Itsik; Daly, Mark J.; Altshuler, David; Stoffel, Markus; Friedman, Jeffrey M.; Breslow, Jan L.
In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 28, No. 11, 01.11.2008, p. 2078-2084.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13
AU - Burkhardt, Ralph
AU - Kenny, Eimear E.
AU - Lowe, Jennifer K.
AU - Birkeland, Andrew
AU - Josowitz, Rebecca
AU - Noel, Martha
AU - Salit, Jacqueline
AU - Maller, Julian B.
AU - Pe'er, Itsik
AU - Daly, Mark J.
AU - Altshuler, David
AU - Stoffel, Markus
AU - Friedman, Jeffrey M.
AU - Breslow, Jan L.
PY - 2008/11/1
Y1 - 2008/11/1
N2 - 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.
AB - 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.
KW - Alternative splicing
KW - Genome-wide association study
KW - HMG-CoA reductase
KW - LDL-C
KW - SNP
UR - http://www.scopus.com/inward/record.url?scp=55449105227&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=55449105227&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.108.172288
DO - 10.1161/ATVBAHA.108.172288
M3 - Article
C2 - 18802019
AN - SCOPUS:55449105227
VL - 28
SP - 2078
EP - 2084
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 11
ER -