title: High HDL cholesterol does not protect against coronary artery disease when associated with combined cholesteryl ester transfer protein and hepatic lipase gene variants.
abstract: Cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are two HDL modifying proteins that have both pro- and anti-atherogenic properties. We hypothesized that CETP and HL synergistically affect HDL cholesterol and atherosclerotic risk. To test our hypothesis, we analysed the genotype frequencies of CETP Taq1B (rs708272) and LIPC-514C/T (rs1800588) polymorphisms in male coronary artery disease patients (CAD; n=792) and non-symptomatic controls (n=539). Cases and controls had similar allele frequencies, but the occurrence of the combined genotypes differed (p=0.027). In CAD patients, 1.3% had the CETP-B2B2/LIPC-TT genotype, with only 0.2% in controls (p=0.033). The presence of the CETP lowering B2 allele and the HL lowering LIPC-T allele synergistically increased HDL cholesterol from 0.87+/-0.19 mmol/L in the B1B1/CC (n=183) to 1.21+/-0.25 mmol/L in the B2B2/TT carriers (n=10). The B1B1/CC carriers had an increased CAD risk (OR 1.4; p=0.025). Despite their high HDL cholesterol, the B2B2/TT individuals also had an increased CAD risk (OR 3.7; p=0.033). In a 2-year follow up, the loss of coronary artery lumen diameter in these patients was higher than in all other patients combined (0.34+/-0.70 versus 0.10+/-0.29 mm; p=0.044). We conclude that a high HDL cholesterol does not protect against coronary artery disease when associated with combined CETP- and HL-lowering gene variants.
authors.affiliation: Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Bernadette A C
authors.initials: BA
authors.lastname: van Acker
authors.forename: Gert-Jan
authors.initials: GJ
authors.lastname: Botma
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
authors.forename: Jolanda M A
authors.initials: JM
authors.lastname: Boer
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Seidell
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Hans
authors.initials: H
authors.lastname: Jansen
authors.forename: Adrie J M
authors.initials: AJ
authors.lastname: Verhoeven
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000235:genetics*; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008049:Lipase / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; C504173:LIPC protein, human; D008049:Lipase