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