Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus

Soo Heon Kwak; Ryan B Hernandez-Cancela; Daniel A DiCorpo; David E Condon; Jordi Merino; Peitao Wu; Jennifer A Brody; Jie Yao; Xiuqing Guo; Fariba Ahmadizar; Mariah Meyer; Murat Sincan; Josep M Mercader; Sujin Lee; Jeffrey Haessler; Ha My T Vy; Zhaotong Lin; Nicole D Armstrong; Shaopeng Gu; Noah L Tsao; Leslie A Lange; Ningyuan Wang; Kerri L Wiggins; Stella Trompet; Simin Liu; Ruth J F Loos; Renae Judy; Philip H Schroeder; Natalie R Hasbani; Maxime M Bos; Alanna C Morrison; Rebecca D Jackson; Alexander P Reiner; JoAnn E Manson; Ninad S Chaudhary; Lynn K Carmichael; Yii-Der Ida Chen; Kent D Taylor; Mohsen Ghanbari; Joyce van Meurs; Achilleas N Pitsillides; Bruce M Psaty; Raymond Noordam; Ron Do; Kyong Soo Park; J Wouter Jukema; Maryam Kavousi; Adolfo Correa; Stephen S Rich; Scott M Damrauer; Catherine Hajek; Nam H Cho; Marguerite R Irvin; James S Pankow; Girish N Nadkarni; Robert Sladek; Mark O Goodarzi; Jose C Florez; Daniel I Chasman; Susan R Heckbert; Charles Kooperberg; Josée Dupuis; Rajeev Malhotra; Paul S de Vries; Ching-Ti Liu; Jerome I Rotter; James B Meigs

doi:10.1101/2023.07.25.23293180

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus

Soo Heon Kwak
, Ryan B Hernandez-Cancela
, Daniel A DiCorpo
, David E Condon
, Jordi Merino
, Peitao Wu
, Jennifer A Brody
, Jie Yao
, Xiuqing Guo
, Fariba Ahmadizar
, Mariah Meyer
, Murat Sincan
, Josep M Mercader
, Sujin Lee
, Jeffrey Haessler
, Ha My T Vy
, Zhaotong Lin
, Nicole D Armstrong
, Shaopeng Gu
, Noah L Tsao

Leslie A Lange, Ningyuan Wang, Kerri L Wiggins, Stella Trompet, Simin Liu, Ruth J F Loos, Renae Judy, Philip H Schroeder, Natalie R Hasbani, Maxime M Bos, Alanna C Morrison, Rebecca D Jackson, Alexander P Reiner, JoAnn E Manson, Ninad S Chaudhary, Lynn K Carmichael, Yii-Der Ida Chen, Kent D Taylor, Mohsen Ghanbari, Joyce van Meurs, Achilleas N Pitsillides, Bruce M Psaty, Raymond Noordam, Ron Do, Kyong Soo Park, J Wouter Jukema, Maryam Kavousi, Adolfo Correa, Stephen S Rich, Scott M Damrauer, Catherine Hajek, Nam H Cho, Marguerite R Irvin, James S Pankow, Girish N Nadkarni, Robert Sladek, Mark O Goodarzi, Jose C Florez, Daniel I Chasman, Susan R Heckbert, Charles Kooperberg, Josée Dupuis, Rajeev Malhotra, Paul S de Vries, Ching-Ti Liu, Jerome I Rotter, James B Meigs

Research output: Working paper › Preprint › Academic

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Abstract

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.

METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.

RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( P<5.0×10 -8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10 -9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10 -9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10 -8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction ( P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( P=1.0×10 -16).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Original language	English
Publisher	medRxiv
Pages	1-37
Number of pages	37
DOIs	https://doi.org/10.1101/2023.07.25.23293180
Publication status	Published - 28 Jul 2023

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2023.07.25.23293180v1.fullSubmitted manuscript, 1.29 MBLicence: CC BY-NC-ND

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Kwak, S. H., Hernandez-Cancela, R. B., DiCorpo, D. A., Condon, D. E., Merino, J., Wu, P., Brody, J. A., Yao, J., Guo, X., Ahmadizar, F., Meyer, M., Sincan, M., Mercader, J. M., Lee, S., Haessler, J., Vy, H. M. T., Lin, Z., Armstrong, N. D., Gu, S., ... Meigs, J. B. (2023). Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. (pp. 1-37). medRxiv. https://doi.org/10.1101/2023.07.25.23293180

@techreport{571904f6345046a0bd9c501eff75bc3e,

title = "Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus",

abstract = "BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.METHODS: From 16 studies of the Cohorts for Heart \& Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2\%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( P<5.0×10 -8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95\% confidence interval (CI) 1.15 - 1.32, P=3.6×10 -9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95\% CI 1.52 - 2.35, P=9.9×10 -9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95\% CI 1.16 - 1.35, P=1.5×10 -8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction ( P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95\% CI 1.12 - 1.16) per 1 standard deviation increase ( P=1.0×10 -16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.",

author = "Kwak, \{Soo Heon\} and Hernandez-Cancela, \{Ryan B\} and DiCorpo, \{Daniel A\} and Condon, \{David E\} and Jordi Merino and Peitao Wu and Brody, \{Jennifer A\} and Jie Yao and Xiuqing Guo and Fariba Ahmadizar and Mariah Meyer and Murat Sincan and Mercader, \{Josep M\} and Sujin Lee and Jeffrey Haessler and Vy, \{Ha My T\} and Zhaotong Lin and Armstrong, \{Nicole D\} and Shaopeng Gu and Tsao, \{Noah L\} and Lange, \{Leslie A\} and Ningyuan Wang and Wiggins, \{Kerri L\} and Stella Trompet and Simin Liu and Loos, \{Ruth J F\} and Renae Judy and Schroeder, \{Philip H\} and Hasbani, \{Natalie R\} and Bos, \{Maxime M\} and Morrison, \{Alanna C\} and Jackson, \{Rebecca D\} and Reiner, \{Alexander P\} and Manson, \{JoAnn E\} and Chaudhary, \{Ninad S\} and Carmichael, \{Lynn K\} and Chen, \{Yii-Der Ida\} and Taylor, \{Kent D\} and Mohsen Ghanbari and \{van Meurs\}, Joyce and Pitsillides, \{Achilleas N\} and Psaty, \{Bruce M\} and Raymond Noordam and Ron Do and Park, \{Kyong Soo\} and Jukema, \{J Wouter\} and Maryam Kavousi and Adolfo Correa and Rich, \{Stephen S\} and Damrauer, \{Scott M\} and Catherine Hajek and Cho, \{Nam H\} and Irvin, \{Marguerite R\} and Pankow, \{James S\} and Nadkarni, \{Girish N\} and Robert Sladek and Goodarzi, \{Mark O\} and Florez, \{Jose C\} and Chasman, \{Daniel I\} and Heckbert, \{Susan R\} and Charles Kooperberg and Jos{\'e}e Dupuis and Rajeev Malhotra and \{de Vries\}, \{Paul S\} and Ching-Ti Liu and Rotter, \{Jerome I\} and Meigs, \{James B\}",

year = "2023",

month = jul,

day = "28",

doi = "10.1101/2023.07.25.23293180",

language = "English",

pages = "1--37",

publisher = "medRxiv",

type = "WorkingPaper",

institution = "medRxiv",

}

Kwak, SH, Hernandez-Cancela, RB, DiCorpo, DA, Condon, DE, Merino, J, Wu, P, Brody, JA, Yao, J, Guo, X, Ahmadizar, F, Meyer, M, Sincan, M, Mercader, JM, Lee, S, Haessler, J, Vy, HMT, Lin, Z, Armstrong, ND, Gu, S, Tsao, NL, Lange, LA, Wang, N, Wiggins, KL, Trompet, S, Liu, S, Loos, RJF, Judy, R, Schroeder, PH, Hasbani, NR, Bos, MM, Morrison, AC, Jackson, RD, Reiner, AP, Manson, JE, Chaudhary, NS, Carmichael, LK, Chen, Y-DI, Taylor, KD, Ghanbari, M, van Meurs, J, Pitsillides, AN, Psaty, BM, Noordam, R, Do, R, Park, KS, Jukema, JW, Kavousi, M, Correa, A, Rich, SS, Damrauer, SM, Hajek, C, Cho, NH, Irvin, MR, Pankow, JS, Nadkarni, GN, Sladek, R, Goodarzi, MO, Florez, JC, Chasman, DI, Heckbert, SR, Kooperberg, C, Dupuis, J, Malhotra, R, de Vries, PS, Liu, C-T, Rotter, JI & Meigs, JB 2023 'Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus' medRxiv, pp. 1-37. https://doi.org/10.1101/2023.07.25.23293180

TY - UNPB

T1 - Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus

AU - Kwak, Soo Heon

AU - Hernandez-Cancela, Ryan B

AU - DiCorpo, Daniel A

AU - Condon, David E

AU - Merino, Jordi

AU - Wu, Peitao

AU - Brody, Jennifer A

AU - Yao, Jie

AU - Guo, Xiuqing

AU - Ahmadizar, Fariba

AU - Meyer, Mariah

AU - Sincan, Murat

AU - Mercader, Josep M

AU - Lee, Sujin

AU - Haessler, Jeffrey

AU - Vy, Ha My T

AU - Lin, Zhaotong

AU - Armstrong, Nicole D

AU - Gu, Shaopeng

AU - Tsao, Noah L

AU - Lange, Leslie A

AU - Wang, Ningyuan

AU - Wiggins, Kerri L

AU - Trompet, Stella

AU - Liu, Simin

AU - Loos, Ruth J F

AU - Judy, Renae

AU - Schroeder, Philip H

AU - Hasbani, Natalie R

AU - Bos, Maxime M

AU - Morrison, Alanna C

AU - Jackson, Rebecca D

AU - Reiner, Alexander P

AU - Manson, JoAnn E

AU - Chaudhary, Ninad S

AU - Carmichael, Lynn K

AU - Chen, Yii-Der Ida

AU - Taylor, Kent D

AU - Ghanbari, Mohsen

AU - van Meurs, Joyce

AU - Pitsillides, Achilleas N

AU - Psaty, Bruce M

AU - Noordam, Raymond

AU - Do, Ron

AU - Park, Kyong Soo

AU - Jukema, J Wouter

AU - Kavousi, Maryam

AU - Correa, Adolfo

AU - Rich, Stephen S

AU - Damrauer, Scott M

AU - Hajek, Catherine

AU - Cho, Nam H

AU - Irvin, Marguerite R

AU - Pankow, James S

AU - Nadkarni, Girish N

AU - Sladek, Robert

AU - Goodarzi, Mark O

AU - Florez, Jose C

AU - Chasman, Daniel I

AU - Heckbert, Susan R

AU - Kooperberg, Charles

AU - Dupuis, Josée

AU - Malhotra, Rajeev

AU - de Vries, Paul S

AU - Liu, Ching-Ti

AU - Rotter, Jerome I

AU - Meigs, James B

PY - 2023/7/28

Y1 - 2023/7/28

N2 - BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( P<5.0×10 -8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10 -9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10 -9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10 -8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction ( P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( P=1.0×10 -16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

AB - BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( P<5.0×10 -8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10 -9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10 -9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10 -8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction ( P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( P=1.0×10 -16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

U2 - 10.1101/2023.07.25.23293180

DO - 10.1101/2023.07.25.23293180

M3 - Preprint

C2 - 37546893

SP - 1

EP - 37

BT - Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus

PB - medRxiv

ER -

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus

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