Objectives: Polymorphisms in the hepatic lipase (LIPC -514C > T) and cholesteryl ester transfer protein (CETP I405V) genes affect 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 it's 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 years 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/L in both genders, while an increased risk of MI was observed only in men (hazard ratio = 1.32 [95% Confidence Interval (C.I.): 1.05-1.66] for CT versus CC and 1.75 [95% C.I.: 1.39-2.20] for TT versus 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/L, 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.