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Epistatic Effect of Cholesteryl Ester Transfer Protein and Hepatic Lipase on Serum High-Density Lipoprotein Cholesterol Levels

Genetic Epidemiology Unit (A.I., Y.S.A., C.M.v.D.), Departments of Epidemiology and Biostatistics (A.H., B.H.C.S., J.C.M.W.), Clinical Genetics (B.A.O.), and Metabolic and Vascular Diseases (E.J.G.S.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; Department of Pharmacovigilance (F.A.S.-T.), The Dutch Medicines Evaluation Board Agency, 2500 BE The Hague, The Netherlands; and Department of Pharmacoepidemiology and Pharmacotherapy (O.H.K., A.-H.M.v.d.Z.), Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Prof. C. M. van Duijn, Department of Epidemiology and Biostatistics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: c.vanduijn{at}erasmusmc.nl.

Objectives: 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).

Design: 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.

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