Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction

Citation
M. Corbex et al., Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction, GENET EPID, 19(1), 2000, pp. 64-80
Citations number
28
Categorie Soggetti
Molecular Biology & Genetics
Journal title
GENETIC EPIDEMIOLOGY
ISSN journal
07410395 → ACNP
Volume
19
Issue
1
Year of publication
2000
Pages
64 - 80
Database
ISI
SICI code
0741-0395(200007)19:1<64:EAABTC>2.0.ZU;2-E
Abstract
An extensive association analysis of a candidate gene for coronary heart di sease, Cholesteryl Ester Transfer Protein (CETP) gene, was performed. Ten p olymorphisms, out of which three were newly identified in regulatory region s, were investigated for association with myocardial infarction (MI) and 2 MI endophenotypes (CETP mass and HDL-cholesterol level) in 568 MI patients and 668 controls. The polymorphisms affecting codon 405 (Ile(405)Val) and t he nucleotide 524 downstream from the stop codon (G(+524)T) were almost com pletely concordant and associated with plasma CETP mass (P < 0.001). The Po lymorphisms -629 (located in promoter). intron1 (Taq1B) and intron7 were al most completely concordant and associated with plasma CETP mass (P < 0.0001 ) and HDL-cholesterol levels (P < 0.0001). This latter association was not found in teetotalers and increased with the quantity of alcohol consumed. H eavy drinkers (>75 g/day) homozygous for the (-628)A allele had a reduced r isk of MI (OR = 0.33, P < 0.02). Subjects both homozygous for (451)Arg and heterozygous for (373)Pro had decreased plasma HDL-cholesterol levels and t his effect increased with alcohol consumption. The results illustrate the c omplexity of polymorphism-phenotype associations. They suggest that the CET P gene may carry several functional polymorphisms. Observed interactions be tween alcohol consumption and polymorphisms associated with HDL-cholesterol level constitute concrete examples of gene-environment interactions. Furth ermore, the pattern of association between HDL-cholesterol levels and the p olymorphisms at codons 373 and 451 illustrated how two polymorphisms may be confounders (in the usual epidemiological sense) one for the other: their marginal effects are neutralized because of linkage disequilibrium and thus are not detectable by standard univariate association analysis. Genet. Epi demiol. 19:64-80, 2000. (C) 2000 Wiley-Liss, Inc.