Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study

• Published in: Nature communications Vol. 15; no. 1; pp. 5302 - 10
• Main Authors: Dunca, Diana, Chopade, Sandesh, Gordillo-Marañón, María, Hingorani, Aroon D., Kuchenbaecker, Karoline, Finan, Chris, Schmidt, Amand F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-06-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 692/308/153; 692/308/2056; 692/4019; Anticholesteremic Agents - therapeutic use; Blood pressure; Blood Pressure - drug effects; Blood Pressure - genetics; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - genetics; Cholesterol; Cholesterol Ester Transfer Proteins - genetics; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Coronary artery disease; Coronary Disease - blood; Coronary Disease - genetics; Density; Drug development; East Asian People - genetics; Female; Heart diseases; High density lipoprotein; Humanities and Social Sciences; Humans; Inhibitors; Lipids; Low density lipoprotein; Male; Mendelian Randomization Analysis; Middle Aged; multidisciplinary; Plasma levels; Polymorphism, Single Nucleotide; Randomization; Science; Science (multidisciplinary); Therapeutic targets; White People - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49109-z

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 low-density lipoprotein cholesterol (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 high-density lipoprotein cholesterol. Despite finding evidence for possible neutral effects of lower CETP levels on LDL-C, systolic blood pressure and pulse pressure in East Asians (interaction
p
-values < 1.6 × 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.
CETP inhibitors are being developed for treatment of coronary heart disease. Here, the authors show that the anticipated beneficial effects of lower plasma levels of CETP are shared among individuals of European and East Asian ancestry.