Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.
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.
Burkhardt
Ralph
R
Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY 10065, USA.
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
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
D008078:Cholesterol, LDL; D006903:Hydroxymethylglutaryl CoA Reductases; D012333:RNA, Messenger
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