Epistatic effect of cholesteryl ester transfer protein and hepatic lipase on serum high-density lipoprotein cholesterol levels.
OBJECTIVE
Polymorphisms in the hepatic lipase (LIPC -514C > T) and cholesteryl ester transfer protein (CETP I405V) genes affect high-density lipoprotein cholesterol (HDL-c) levels, but their relationship with cardiovascular disease and their combined effect is unclear. The objectives of the current study were to characterize the effect of the hepatic lipase variant, and its interaction with the CETP variant, in terms of cholesterol levels, atherosclerosis, and risk of myocardial infarction (MI).


METHODS
The study was conducted in the Rotterdam Study, a large single-center prospective cohort study in people aged 55 yr and older. Lipid levels were analyzed using linear regression models, and risk of MI was assessed with Cox proportional hazards models.


RESULTS
The hepatic lipase variant was associated with an increase in serum HDL-c levels of 0.11 mmol/liter in both genders, whereas an increased risk of MI was observed only in men [hazard ratio, 1.32 (95% confidence interval, 1.05-1.66) for CT vs. CC and 1.75 (95% confidence interval, 1.39-2.20) for TT vs. CC]. This effect was independent of serum HDL-c. LIPC -514C > T interacted with CETP I405V with respect to serum HDL-c concentrations. Those homozygous for both mutations saw a marked elevation in HDL-c levels (0.29 mmol/liter, P(interaction) = 0.05). These increased HDL-c levels, however, were not inversely associated with atherosclerosis or MI risk.


CONCLUSIONS
LIPC genotype affects HDL-c levels and risk of MI in males. The interaction of this variant with CETP on HDL-c levels helps elucidate the underlying mechanisms and suggests that the beneficial effects of CETP inhibition may vary in particular subgroups.
Isaacs
Aaron
A
Genetic Epidemiology Unit, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
Aulchenko
Yurii S
YS
Hofman
Albert
A
Sijbrands
Eric J G
EJ
Sayed-Tabatabaei
Fakhredin A
FA
Klungel
Olaf H
OH
Maitland-van der Zee
Anke-Hilse
AH
Stricker
Bruno H Ch
BH
Oostra
Ben A
BA
Witteman
Jacqueline C M
JC
van Duijn
Cornelia M
CM
D000368:Aged; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D009203:Myocardial Infarction / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
D053480:Cholesterol Ester Transfer Proteins; C504173:LIPC protein, human; D008075:Lipoproteins, HDL; D008049:Lipase