Hepatic lipase and CETP gene variants interact to raise HDL-C, but the combined genotype does not lower cardiovascular risk (J Clin Endocrinol Metab 2007)

Original title: Epistatic effect of cholesteryl ester transfer protein and hepatic lipase on serum high-density lipoprotein cholesterol levels

J Clin Endocrinol Metab · 17 April 2007 · 7

Isaacs A, Aulchenko YS, Hofman A, Sijbrands EJ, Sayed-Tabatabaei FA, Klungel OH, Maitland-van der Zee AH, Stricker BH, Oostra BA, Witteman JC, van Duijn CM

In the Rotterdam Study, a prospective cohort of people 55 and older, the hepatic lipase LIPC -514C to T variant raised serum HDL cholesterol by 0.11 mmol/L in both sexes, yet was associated with increased myocardial infarction risk in men (hazard ratio 1.32 for CT versus CC, 1.75 for TT versus CC), independent of HDL-C. LIPC interacted with the CETP I405V variant: individuals homozygous for both mutations showed a further HDL-C elevation of 0.29 mmol/L (P for interaction = 0.05). Despite these higher HDL-C levels, the doubly homozygous genotype was not inversely associated with atherosclerosis or myocardial infarction risk, adding early genetic evidence that HDL-C raised through this specific gene combination does not necessarily translate into cardiovascular protection.

Original abstract

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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.