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

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; Hong Kong Diabetes Biobank Study Group; TRANSCEND Consortium (TRansomics ANalysis of Complications and ENdpoints in Diabetes)

doi:10.2337/dc22-2331

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

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^*, Hong Kong Diabetes Biobank Study Group, TRANSCEND Consortium (TRansomics ANalysis of Complications and ENdpoints in Diabetes)

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

11 Citations (Scopus)

Abstract

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 (P_interaction = 0.0155) and myocardial infarction (MI) (P_interaction = 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 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. © 2023 by the American Diabetes Association.

Original language	English
Pages (from-to)	1271-1281
Journal	Diabetes Care
Volume	46
Issue number	6
Online published	1 May 2023
DOIs	https://doi.org/10.2337/dc22-2331
Publication status	Published - Jun 2023

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SDG 3 Good Health and Well-being

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Tam, C. H. T., Lim, C. K. P., Luk, A. O. Y., Shi, M., Man Cheung, H., Ng, A. C. W., Lee, H., Lau, E. S. H., Fan, B., Jiang, G., Kong, A. P. S., Ozaki, R., Chow, E. Y. K., Lee, K. F., Siu, S. C., Hui, G., Tsang, C. C., Lau, K. P., Leung, J. Y. Y., ... TRANSCEND Consortium (TRansomics ANalysis of Complications and ENdpoints in Diabetes) (2023). 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. Diabetes Care, 46(6), 1271-1281. https://doi.org/10.2337/dc22-2331

@article{5f43cd448aa94fbdb25ffc8231594819,

title = "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",

abstract = "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 >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 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. {\textcopyright} 2023 by the American Diabetes Association.",

author = "Tam, \{Claudia H.T.\} and Lim, \{Cadmon K.P.\} and Luk, \{Andrea O.Y.\} and Mai Shi and \{Man Cheung\}, Hoi and Ng, \{Alex C.W.\} and Heung-man Lee and Lau, \{Eric S.H.\} and Baoqi Fan and Guozhi Jiang and Kong, \{Alice P.S.\} and Risa Ozaki and Chow, \{Elaine Y.K.\} and Lee, \{Ka Fai\} and Siu, \{Shing Chung\} and Grace Hui and Tsang, \{Chiu Chi\} and Lau, \{Kam Piu\} and Leung, \{Jenny Y.Y.\} and Cheung, \{Elaine Y.N.\} and Tsang, \{Man Wo\} and Grace Kam and Lau, \{Ip Tim\} and Li, \{June K.Y.\} and Yeung, \{Vincent T.F.\} and Emmy Lau and Stanley Lo and Samuel Fung and Cheng, \{Yuk Lun\} and Chow, \{Chun Chung\} and Xiaodan Fan and Chan, \{Ting Fung\} and Yip, \{Kevin Y.L.\} and Si Lok and Weichuan Yu and Tsui, \{Stephen K.W.\} and Hui-yao Lan and Szeto, \{Cheuk Chun\} and Tang, \{Nelson L.S.\} and Brian Tomlinson and Yu Huang and Jenkins, \{Alicia J.\} and Anthony Keech and Wing-yee So and Chan, \{Juliana C.N.\} and Ma, \{Ronald C.W.\} and \{Hong Kong Diabetes Biobank Study Group\} and \{TRANSCEND Consortium (TRansomics ANalysis of Complications and ENdpoints in Diabetes)\}",

year = "2023",

month = jun,

doi = "10.2337/dc22-2331",

language = "English",

volume = "46",

pages = "1271--1281",

journal = "Diabetes Care",

issn = "1935-5548",

publisher = "American Diabetes Association",

number = "6",

}

Tam, CHT, Lim, CKP, Luk, AOY, Shi, M, Man Cheung, H, Ng, ACW, Lee, H, Lau, ESH, Fan, B, Jiang, G, Kong, APS, Ozaki, R, Chow, EYK, Lee, KF, Siu, SC, Hui, G, Tsang, CC, Lau, KP, Leung, JYY, Cheung, EYN, Tsang, MW, Kam, G, Lau, IT, Li, JKY, Yeung, VTF, Lau, E, Lo, S, Fung, S, Cheng, YL, Chow, CC, Fan, X, Chan, TF, Yip, KYL, Lok, S, Yu, W, Tsui, SKW, Lan, H, Szeto, CC, Tang, NLS, Tomlinson, B, Huang, Y, Jenkins, AJ, Keech, A, So, W, Chan, JCN, Ma, RCW, Hong Kong Diabetes Biobank Study Group & TRANSCEND Consortium (TRansomics ANalysis of Complications and ENdpoints in Diabetes) 2023, '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', Diabetes Care, vol. 46, no. 6, pp. 1271-1281. https://doi.org/10.2337/dc22-2331

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. / Tam, Claudia H.T.; Lim, Cadmon K.P.; Luk, Andrea O.Y. et al.
In: Diabetes Care, Vol. 46, No. 6, 06.2023, p. 1271-1281.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - 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

AU - Tam, Claudia H.T.

AU - Lim, Cadmon K.P.

AU - Luk, Andrea O.Y.

AU - Shi, Mai

AU - Man Cheung, Hoi

AU - Ng, Alex C.W.

AU - Lee, Heung-man

AU - Lau, Eric S.H.

AU - Fan, Baoqi

AU - Jiang, Guozhi

AU - Kong, Alice P.S.

AU - Ozaki, Risa

AU - Chow, Elaine Y.K.

AU - Lee, Ka Fai

AU - Siu, Shing Chung

AU - Hui, Grace

AU - Tsang, Chiu Chi

AU - Lau, Kam Piu

AU - Leung, Jenny Y.Y.

AU - Cheung, Elaine Y.N.

AU - Tsang, Man Wo

AU - Kam, Grace

AU - Lau, Ip Tim

AU - Li, June K.Y.

AU - Yeung, Vincent T.F.

AU - Lau, Emmy

AU - Lo, Stanley

AU - Fung, Samuel

AU - Cheng, Yuk Lun

AU - Chow, Chun Chung

AU - Fan, Xiaodan

AU - Chan, Ting Fung

AU - Yip, Kevin Y.L.

AU - Lok, Si

AU - Yu, Weichuan

AU - Tsui, Stephen K.W.

AU - Lan, Hui-yao

AU - Szeto, Cheuk Chun

AU - Tang, Nelson L.S.

AU - Tomlinson, Brian

AU - Huang, Yu

AU - Jenkins, Alicia J.

AU - Keech, Anthony

AU - So, Wing-yee

AU - Chan, Juliana C.N.

AU - Ma, Ronald C.W.

AU - Hong Kong Diabetes Biobank Study Group

AU - TRANSCEND Consortium (TRansomics ANalysis of Complications and ENdpoints in Diabetes)

PY - 2023/6

Y1 - 2023/6

N2 - 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 >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 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. © 2023 by the American Diabetes Association.

AB - 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 >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 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. © 2023 by the American Diabetes Association.

UR - https://www.scopus.com/pages/publications/85160003298

UR - https://www.scopus.com/pages/publications/85160003298#tab=impact

U2 - 10.2337/dc22-2331

DO - 10.2337/dc22-2331

M3 - RGC 21 - Publication in refereed journal

C2 - 37125963

SN - 1935-5548

VL - 46

SP - 1271

EP - 1281

JO - Diabetes Care

JF - Diabetes Care

IS - 6

ER -

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

Abstract

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