CETP loss-of-function variant fails to affect CVD risk

NEW ORLEANS — Despite altering lipid metabolism, a loss-of-function variant of the CETP gene did not affect risk for occlusive CVD, ischemic stroke or major coronary events, according to a presentation at the American Heart Association Scientific Sessions.

Zhengming Chen, DPhil, from the University of Oxford, and colleagues from the China Kadoorie Biobank Collaborative Group assessed whether the loss-of-function variant present in some East Asian individuals, rs2303790, and concomitant lifelong lower activity of cholesterol ester transport protein (CETP), affected risk for CVD.

The variant mimics pharmacological inhibition of the CETP protein, but drugs designed to inhibit CETP and raise HDL have not demonstrated an impact on CVD risk, although a major trial is still underway, Chen said.

Among the 512,891 adults aged 30 to 79 years recruited for the China Kadoorie Biobank, the variant was genotyped in 91,850 individuals, of which 17,850 had conventional lipid measurements and 4,650 had lipoprotein subtypes measured, Chen said.

Chen and colleagues constructed linear and logistic regression models to determine adjusted per-allele effects for continuous traits, as well as for 11,650 occlusive CVD events (75% ischemic strokes).

The loss-of-function variant was linked to an increase of 0.53 standard deviations per allele (95% CI, 0.45-0.6) in HDL, approximately the same as a rise of 6.1 mg/dL, but had no effect on LDL concentration, according to the researchers.

The effect of the variant on circulation metabolites included larger particle size of HDL, smaller particle size of LDL, increased cholesterol esters within HDL particles and reduced triglycerides relative to total lipids, Chen said.

However, he said, there was no significant relationship between the variant and risk for occlusive CVD (OR per allele = 1.04; 95% CI, 0.94-1.16), ischemic stroke (OR per allele = 1.02; 95% CI, 0.9-1.15) or major coronary events (OR per allele = 1.17; 95% CI, 0.98-1.39). Nor was there an association with hemorrhagic stroke, in contrast with a recent CETP genetic study that used different CETP genetic variants (Anderson CD, et al. Ann Neurol. 2016;doi:10.1002/ana.24780), Chen said.

The variant conferred excess risk for fatal occlusive vascular events (OR per allele = 1.27; 95% CI, 1.02-1.57) and eye diseases (OR = 1.33; 95% CI, 1.13-1.56), according to the researchers.

“In East Asians, increasing HDL by CETP inhibition is unlikely to confer appreciable protection against CVD, although pharmacologic agents may affect risk in other ways, for example through LDL lowering in addition to HDL raising,” Chen said during the presentation. – by Erik Swain

Reference:

Chen Z, et al. CSSR.02 – Precision Medicine on the Front Lines. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.

Disclosure: The study was funded in part by Merck. Chen reports receiving a research grant from Merck.