title: Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.
abstract: Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5-7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4 × 10(-5), allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8 × 10(-10)) and intron 8 polymorphism rs9930761-T>C (5.6 × 10(-8)) (in high linkage disequilibrium with allele frequencies 6-7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9.The effect of these polymorphisms was evaluated in two clinical studies. In the Whitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independently associated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6 × 10(-28) and rs5883 p = 8.6 × 10(-10), adjusted for rs247616). In an independent multiethnic US cohort of hypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associated with increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29-4.30), p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar to earlier results linking low CETP activity with poor outcomes in males, our results suggest genetic, sex-dependent CETP splicing effects on cardiovascular risk by a mechanism independent of circulating HDL-C levels.
authors.affiliation: Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Audrey C
authors.initials: AC
authors.lastname: Papp
authors.forename: Julia K
authors.initials: JK
authors.lastname: Pinsonneault
authors.forename: Danxin
authors.initials: D
authors.lastname: Wang
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Newman
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
mesh_terms: D000328:Adult; D000483:Alleles; D001262:Atenolol / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D012727:Sex Characteristics; D014700:Verapamil / Q000627:therapeutic use
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D020033:Protein Isoforms; D012333:RNA, Messenger; D001262:Atenolol; D014700:Verapamil