Dunca, Diana;
Choapde, Sandesh;
Gordillo-Maranon, Maria;
Hingorani, Aaron;
Kuchenbaecker, Karoline;
Finan, Chris;
Schmidt, Amand Floriaan;
(2023)
Comparing the Effect Profile of CETP in Individuals of East Asian and European Ancestries.
Presented at: American-Heart-Association's Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions, PA, Philadelphia.
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Abstract
Introduction: Cholesteryl ester transfer protein (CETP) is a lipid drug target under development for CHD in both European and East Asian populations.Previous drug target Mendelian randomization (MR) studies conducted in East Asians failed to show a CHD effect, which has been interpreted as lack of effectiveness of CETP inhibition for CHD prevention in this population. Hypothesis: In this study, we inferred the effect of CETP inhibition in individuals of European and East Asian ancestries using drug target Mendelian randomization. Methods: We leveraged genetic associations of CETP variants with major blood lipid fractions for individuals of European (n=1,320,016) and East Asian (n=146,492) ancestries. Colocalization was employed to identify potential cross-ancestry signals of CETP variants for plasma concentrations of LDL-C or HDL-C. Drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition. Differences between ancestries were evaluated using interaction tests, applying a multiplicity corrected alpha of 1.9х10-3 based on the 26 considered traits. Results: There was strong support (posterior probability=1.00) of a shared causal CETP variant affecting HDL-C in both populations, which was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP was associated with lower LDL-C, Lp[a], systolic blood pressure and pulse pressure in both groups, but the effects were more pronounced in European individuals (interaction p-values < 1.9х10-3). Lower CETP was protective against CHD, angina, intracerebral haemorrhage and heart failure in both ancestries, for example for CHD in East Asians (OR 0.89, 95%CI 0.84;0.94) compared to Europeans (OR 0.95, 95%CI 0.92;0.99, interaction p-value=0.05). Conclusions: In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.
| Type: | Conference item (Presentation) |
|---|---|
| Title: | Comparing the Effect Profile of CETP in Individuals of East Asian and European Ancestries |
| Event: | American-Heart-Association's Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions |
| Location: | PA, Philadelphia |
| Dates: | 11 Nov 2023 - 13 Nov 2023 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1161/circ.148.suppl_1.14019 |
| Publisher version: | https://doi.org/10.1161/circ.148.suppl_1.14019 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Peripheral Vascular Disease, Cardiovascular System & Cardiology, CETP, Cardiovascular disease, Coronary heart disease, LDL |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10204576 |
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