Drug target Mendelian randomisation to compare the effects of cholesteryl ester transfer protein (CETP) in individuals of East Asian and European ancestries
CETP correlation matrices in the East Asian and European populations (GRCh37) used for linkage disequilibrium pruning. These correlation matrices and summary statistics for LDL-C and HDL-C from Global Lipids Genetics Consortium (GLGC 2021) were used to generate ancestry specific CETP locus zoom plots.
CETP inhibitors are a class of lipid-lowering drugs in development for treatment of coronary heart disease (CHD). Genetic studies in East Asian ancestry have interpreted the lack of CETP signal with LDL-C and lack of drug target Mendelian randomization (MR) effect on CHD as evidence that CETP inhibitors might not be effective in East Asian participants. Capitalizing on recent increases in sample size of East Asian genetic studies, we conducted a drug target MR analysis, scaled to a standard deviation increase in HDL-C. Despite finding evidence for a possible absence of effect of lower CETP levels on LDL-C, systolic blood pressure and pulse pressure in East Asians (interaction p-values < 1.8×10-3), effects on cardiovascular outcomes were similarly protective in both ancestry groups. In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.