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 journalArticle

91 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2078-2084
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number11
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

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Alternative Splicing
LDL Cholesterol
Single Nucleotide Polymorphism
Genome-Wide Association Study
Messenger RNA
Alleles
Genome
Gene-Environment Interaction
Linkage Disequilibrium
Coenzyme A
Population
Genes
Transfection
Oxidoreductases

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 journalArticle

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 2008, 'Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, pp. 2078-2084. https://doi.org/10.1161/ATVBAHA.108.172288
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. / Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2008 ; Vol. 28, No. 11. pp. 2078-2084.
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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.",
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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

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