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
Authors: Tam Claudia H.T. , Lim Cadmon K.P. , Luk Andrea O.Y. , Shi Mai , Man Cheung Hoi , Ng Alex C.W. , Lee Heung-man , Lau Eric S.H. , Fan Baoqi , Jiang Guozhi , Kong Alice P.S. , Ozaki Risa , Chow Elaine Y.K. , Lee Ka Fai , Siu Shing Chung , Hui Grace , Tsang Chiu Chi , Lau Kam Piu , Leung Jenny Y.Y. , Cheung Elaine Y.N. , Tsang Man Wo , Kam Grace , Lau Ip Tim , Li June K.Y. , Yeung Vincent T.F. , Lau Emmy , Lo Stanley , Fung Samuel , Cheng Yuk Lun , Chow Chun Chung , Fan Xiaodan , Chan Ting Fung , Yip Kevin Y.L. , Lok Si , Yu Weichuan , Tsui Stephen K.W. , Lan Hui-yao , Szeto Cheuk Chun , Tang Nelson L.S. , Tomlinson Brian , Huang Yu , Jenkins Alicia J. , Keech Anthony , So Wing-yee , Chan Juliana C.N. , Ma Ronald C.W. ,   Hong Kong Diabetes Biobank Study Group, FIELD Study Investigators, Ma Ronald C.W. , Chan Juliana C.N. , Ozaki Risa , Luk Andrea O.Y. , So Wingyee , Lee Ka-fai , Siu Shing-chung , Hui Grace , Tsang Chiu-chi , Lau Kam-piu , Leung Jenny Y.Y. , Tsang Man-wo , Kam Grace , Cheung Elaine , Lau Ip-tim , Li June K.Y. , Yeung Vincent T.F. , Kwan Jo Jo , Fung Samuel , Lo Stanley , Lau Emmy , Cheng Yuk-lun , Tsui Stephen K.W. , Huang Yu , Lan Huiyao , Yu Weichuan , Tomlinson Brian , Lok Si , Chan Ting-fung , Yip Kevin Y.L. , Szeto Cheuk-chun , Fan Xiaodan , Tang Nelson L.S. , Tian Xiaoyu , Tam Claudia H.T. , Jiang Guozhi , Mai Shi , Fan Baoqi , Xie Fei , Zhang Sen , Yu Pu , Wang Meng , Lee Heung-man , Lim Cadmon K.P. , Xie Fangying , Ng Alex C.W. , Cheung Grace P.Y. , Kong Alice P.S. , Chow Elaine Y.K. , Yeung Ming-wai , Chow Chun-chung , Cheung Kitty K.T. , Wong Rebecca Y.M. , So Honcheong , Chan Katie K.H. , Law Chin-san , Lock Anthea K.Y. , Tsang Ingrid K.Y. , Chan Susanna C.P. , Chan Yin-wah , Chiu Cherry , Hung Chi-sang , Ho Cheuk-wah , Ng Ivy H.Y. , Mak Maria W.H. , Lee Kai-man , Leung Candy H.S. , Lee Ka-wah , Chan Hui-ming , Wat Winnie , Lau Tracy , Law Cheuk-yiu , Chan Ryan H.Y. , Lau Candice , Tsang Pearl , Chan Vince , Ho Lap-ying , Wong Eva , Chan Josephine , Lam Sau-fung , Pang Jessy , Lee Yee-mui ,   TRansomics ANalysis of Complications and ENdpoints in Diabetes (TRANSCEND) Consortium, Ma Ronald C.W. , Chan Juliana C.N. , Huang Yu , Lan Hui-yao , Lok Si , Tomlinson Brian , Tsui Stephen K.W. , Yu Weichuan , Yip Kevin Y.L. , Chan Ting-fung , Fan Xiaodan , So Wing-yee , Szeto Cheuk-chun , Tang Nelson L.S. , Luk Andrea O.Y. , Tian Xiaoyu , Tam Claudia H.T. , Jiang Guozhi , Lee Heung Man , Lim Cadmon K.P. , Chan Katie K.H. , Xie Fangying , Ng Alex C.W. , Cheung Grace P.Y. , Yeung Ming-wai , Mai Shi , Xie Fei , Jiang Wei , Zhang Sen , Yu Pu , Weng Meng , Li Kelly Y. , Huang Chuiguo , Yu Gechang 
Published: May 2023

OBJECTIVE
In this study we aim 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 study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) 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 glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases.

RESULTS
We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 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 &gt;40% reduction in either cardiovascular events in response to BP control (2.9 × 10−8 &lt; P &lt; 3.6 × 10−5), those with CT genotype had no difference (0.0726 &lt; P &lt; 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 that 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.