title: 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.
  
  
  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%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.
  
  
  CONCLUSIONS
  We identified variants in HMGCR that are associated with LDL-C across populations and affect alternative splicing of HMGCR exon13.
authors.affiliation: Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Burkhardt
authors.forename: Eimear E
authors.initials: EE
authors.lastname: Kenny
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lowe
authors.forename: Andrew
authors.initials: A
authors.lastname: Birkeland
authors.forename: Rebecca
authors.initials: R
authors.lastname: Josowitz
authors.forename: Martha
authors.initials: M
authors.lastname: Noel
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Salit
authors.forename: Julian B
authors.initials: JB
authors.lastname: Maller
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
authors.forename: Jan L
authors.initials: JL
authors.lastname: Breslow
mesh_terms: D000818:Animals; D006224:Cricetinae; D006801:Humans; D017398:Alternative Splicing; D016466:CHO Cells; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D003412:Cricetulus; D005091:Exons; D005838:Genotype; D006720:Homozygote; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008214:Lymphocytes / Q000201:enzymology; D008849:Micronesia; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D044465:White People / Q000235:genetics; D000095188:Pacific Island People / Q000235:genetics
chemical_list: D008078:Cholesterol, LDL; D006903:Hydroxymethylglutaryl CoA Reductases; D012333:RNA, Messenger
references.citation: Circulation. 2008 Mar 25;117(12):1537-44
references.pmid: 18332269
references.citation: Nat Rev Genet. 2008 Apr;9(4):314-8
references.pmid: 18283274
references.citation: Nature. 1990 Feb 1;343(6257):425-30
references.pmid: 1967820
references.citation: EMBO J. 2000 Mar 1;19(5):819-30
references.pmid: 10698924
references.citation: Lancet. 2000 Feb 26;355(9205):675-87
references.pmid: 10703799
references.citation: Hum Hered. 2001;51(1-2):8-19
references.pmid: 11096265
references.citation: Annu Rev Genet. 2000;34:233-254
references.pmid: 11092828
references.citation: Trends Genet. 2002 Apr;18(4):186-93
references.pmid: 11932019
references.citation: Am J Med Genet. 2002 Jul 1;110(3):234-42
references.pmid: 12116231
references.citation: J Clin Invest. 2003 Jun;111(12):1795-803
references.pmid: 12813012
references.citation: Science. 2003 Dec 19;302(5653):2141-4
references.pmid: 14684825
references.citation: Am J Hum Genet. 2004 Apr;74(4):610-22
references.pmid: 15015130
references.citation: JAMA. 2004 Jun 16;291(23):2821-7
references.pmid: 15199031
references.citation: Biochemistry. 1976 Feb 10;15(3):521-8
references.pmid: 1252410
references.citation: J Lipid Res. 1979 Jan;20(1):40-6
references.pmid: 438654
references.citation: J Biol Chem. 1982 Dec 25;257(24):14639-41
references.pmid: 6897404
references.citation: J Biol Chem. 1983 Nov 25;258(22):13875-81
references.pmid: 6643457
references.citation: J Clin Invest. 1984 Sep;74(3):867-79
references.pmid: 6470142
references.citation: N Engl J Med. 1993 Apr 22;328(16):1150-6
references.pmid: 8455681
references.citation: J Biol Chem. 1999 Jun 11;274(24):17171-8
references.pmid: 10358074
references.citation: Nat Rev Mol Cell Biol. 2005 May;6(5):386-98
references.pmid: 15956978
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3502-9
references.pmid: 16537441
references.citation: BMC Mol Biol. 2007;8:3
references.pmid: 17233885
references.citation: Science. 2007 Jun 1;316(5829):1331-6
references.pmid: 17463246
references.citation: PLoS One. 2007;2(9):e841
references.pmid: 17786212
references.citation: Am J Hum Genet. 2008 Jan;82(1):139-49
references.pmid: 18179892
references.citation: Nat Genet. 2008 Feb;40(2):161-9
references.pmid: 18193043
references.citation: Nat Genet. 2008 Feb;40(2):189-97
references.pmid: 18193044
references.citation: Lancet. 2008 Feb 9;371(9611):483-91
references.pmid: 18262040
references.citation: Nat Rev Genet. 2008 May;9(5):356-69
references.pmid: 18398418