American Diabetes Association
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Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes

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posted on 2023-05-04, 11:54 authored by Claudia H.T. Tam, Cadmon K.P. Lim, Andrea O.Y. Luk, Mai Shi, Hoi Man Cheung, Alex C.W. Ng, Heung-man Lee, Eric S.H. Lau, Baoqi Fan, Guozhi Jiang, Alice P.S. Kong, Risa Ozaki, Elaine Y.K. Chow, Ka Fai Lee, Shing Chung Siu, Grace Hui, Chiu Chi Tsang, Kam Piu Lau, Jenny Y.Y. Leung, Elaine Y.N. Cheung, Man Wo Tsang, Grace Kam, Ip Tim Lau, June K.Y. Li, Vincent T.F. Yeung, Emmy Lau, Stanley Lo, Samuel Fung, Yuk Lun Cheng, Chun Chung Chow, Xiaodan Fan, Ting Fung Chan, Kevin Y.L. Yip, Si Lok, Weichuan Yu, Stephen K.W. Tsui, Hui-yao Lan, Cheuk Chun Szeto, Nelson L.S. Tang, Brian Tomlinson, Yu Huang, Alicia J Jenkins, Anthony Keech, Wing-yee So, Juliana C.N. Chan, Ronald C.W. Ma, The Hong Kong Diabetes Biobank Study Group, FIELD Study investigators, The TRANSCEND Consortium

 Objective: This study aims to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications.

Research Design and Methods: We performed a two-stage genome-wide association studies for CHD in Chinese patients with T2D (3,596 cases and 8,898 controls), followed by replications in European patients with T2D (764 cases and 4,276 controls) and general populations (n=51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes, and its interactions with glycaemic, blood pressure (BP) and lipid controls on incident cardiovascular diseases. 

Results: We identified a novel variant (rs10171703) for CHD (OR [95% CI] = 1.21 [1.13–1.30]; P=2.4×10-8) and BP (β±SE = 0.130±0.017; P = 4.1×10-14) at PDE1A in Chinese T2D patients, but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1×10-4). Patients with CC-genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9×10-8 < P < 3.6×10-5), those with CT-genotype had no difference (0.0726 < P < 0.2614), and those with TT-genotype had a threefold increase in MI risk (P = 6.7×10-3). 

Conclusions: We discovered a novel CHD- and BP-related variant at PDE1A which interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes only when our findings are validated. 


This work was funded by 1) the Research Grants Council of the Hong Kong Special Administrative Region (CU R4012-18), 2) the Research Grants Council Theme-based Research Scheme (T12-402/13N), 3) the Focused Innovation Scheme, Vice-Chancellor One-off Discretionary Fund, 4) University Grants Committee Research Grants Matching Scheme, 5) the Postdoctoral Fellowship Scheme of the Chinese University of Hong Kong, 5) the Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Fund, 6) Natural Science Foundation of China – National Health and Medical Science Council, Australia Joint Research Scheme (No. 81561128017), and 7) the Hong Kong Foundation for Research and Development in Diabetes, the Chinese University of Hong Kong, 8) the Croucher Foundation Senior Medical Research Fellowship, and 9) Research Grants Council Senior Research Fellow (SRFS2021-4S04). The funding sources did not have any role in the design, interpretation of the study, or the decision to publish the results.