CETP gene variants and risk of vascular and non-vascular diseases in ~150,000 Chinese adults

Importance Raising HDL-cholesterol through pharmacological inhibition of cholesteryl ester transfer protein is a potentially important strategy for prevention and treatment of cardiovascular diseases. Objective To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower cholesteryl ester transfer protein activity on cardiovascular diseases and other outcomes. Design A prospective biobank study, with 9-year follow-up through linkage to health insurance records and death and disease registries. Setting Five urban and five rural areas of China. Participants 151,217 individuals aged 30-79 years at baseline with genotype data, 17,854 of whom also had lipid measurements and 4,657 had lipoprotein particle measurements. Exposures Five CETP variants including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to effects on HDL-cholesterol. Main outcomes and measure Baseline lipids and lipoprotein particles, cardiovascular risk factors, and incidence of carotid plaque and pre-defined major vascular and non-vascular diseases and a phenome-wide range of diseases. Results Overall the mean LDL-cholesterol was 91 and HDL-cholesterol was 48 mg/dL. CETP variants were strongly associated with higher concentrations of HDL-cholesterol (e.g. 6.1 mg/dL per rs2303790 allele; P=9.4x10-4766 ), but were not associated with lower LDL-cholesterol. Within HDL particles, cholesterol esters were increased and triglycerides reduced, while within VLDL particles, cholesterol esters were reduced and triglycerides increased. Scaled to 10mg/dL higher HDL-cholesterol, the CETP genetic score was not associated with occlusive cardiovascular disease (18,550 events; OR=0.98 [95%CI 0.91-1.06]), major coronary events (5,767 events; 1.08 [0.95-1.22]), myocardial infarction (3,118 events; 1.14 [0.97-1.34]) ischemic stroke (13,759 events; 0.94 [0.83-1.06]), intracerebral haemorrhage (6,532 events; 0.94 [0.86-1.02]) or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. There were no associations with non-vascular diseases other than an increased risk of eye diseases with rs2303790 (4,090 events; 1.43 [1.13-1.80], P=0.0028). Conclusions and relevance CETP variants were associated with altered HDL metabolism but did not lower LDL-cholesterol and had no significant effects on cardiovascular disease risk. These results suggest that in the absence of reduced LDL-cholesterol, increasing HDL-cholesterol by inhibition of cholesteryl ester transfer protein may not confer significant benefits for cardiovascular diseases.