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Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.
Sunday,2023-08-20 20:12 America/Los_Angeles — ecterry
| Title | Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. |
| Publication Type | Journal Article |
| Year of Publication | 2023 |
| Authors | Kwak, SHeon, 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, HMy T, 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, JAE, Chaudhary, NS, Carmichael, LK, Chen, Y-DI, Taylor, KD, Ghanbari, M, van Meurs, J, Pitsillides, AN, Psaty, BM, Noordam, R, Do, R, Park, KSoo, J Jukema, W, 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 |
| Journal | medRxiv |
| Date Published | 2023 Jul 28 |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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 ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <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 ( =1.0×10 ).</p><p><b>CONCLUSIONS: </b>The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.</p><p><b>CLINICAL PERSPECTIVE: </b> We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.</p> |
| DOI | 10.1101/2023.07.25.23293180 |
| Alternate Journal | medRxiv |
| PubMed ID | 37546893 |
| PubMed Central ID | PMC10402212 |
| Grant List | 75N92021D00005 / WH / WHI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States R01 HL159514 / HL / NHLBI NIH HHS / United States N01HC95165 / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States 75N92020D00002 / HL / NHLBI NIH HHS / United States 75N92021D00002 / HL / NHLBI NIH HHS / United States HHSN268201500003C / HL / NHLBI NIH HHS / United States HHSN268201800012I / HB / NHLBI NIH HHS / United States HHSN268201800012C / HL / NHLBI NIH HHS / United States 75N92020D00005 / HL / NHLBI NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States N01HC95163 / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States HHSN268201500001C / HL / NHLBI NIH HHS / United States UL1 TR001079 / TR / NCATS NIH HHS / United States UL1 TR001878 / TR / NCATS NIH HHS / United States HHSN268201800014I / HB / NHLBI NIH HHS / United States R01 HL043851 / HL / NHLBI NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States S10 OD028685 / OD / NIH HHS / United States R01 HL085251 / HL / NHLBI NIH HHS / United States 75N92020D00001 / HL / NHLBI NIH HHS / United States N01HC95169 / HL / NHLBI NIH HHS / United States N01HC95164 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N02HL64278 / HL / NHLBI NIH HHS / United States T32 HL007457 / HL / NHLBI NIH HHS / United States HHSN268201800014C / HL / NHLBI NIH HHS / United States N01HC95162 / HL / NHLBI NIH HHS / United States R01 HL136666 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States 75N92020D00003 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States N01HC95168 / HL / NHLBI NIH HHS / United States 75N92021D00001 / HL / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R01 DK109588 / DK / NIDDK NIH HHS / United States R01 HL146860 / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201800001C / HL / NHLBI NIH HHS / United States HHSN268201800013I / MD / NIMHD NIH HHS / United States IK2 CX001780 / CX / CSRD VA / United States U01 NS041588 / NS / NINDS NIH HHS / United States N01HC95159 / HL / NHLBI NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States 75N92021D00003 / WH / WHI NIH HHS / United States U01 HG011723 / HG / NHGRI NIH HHS / United States N01HC95161 / HL / NHLBI NIH HHS / United States UL1 TR001420 / TR / NCATS NIH HHS / United States 75N92020D00004 / HL / NHLBI NIH HHS / United States UM1 CA182913 / CA / NCI NIH HHS / United States HHSN268201800011C / HL / NHLBI NIH HHS / United States 75N92020D00007 / HL / NHLBI NIH HHS / United States T32 GM100842 / GM / NIGMS NIH HHS / United States R01 CA047988 / CA / NCI NIH HHS / United States HHSN268201500003I / HL / NHLBI NIH HHS / United States 75N92021D00006 / HL / NHLBI NIH HHS / United States R01 HL080467 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC95167 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States HHSN268201800015I / HB / NHLBI NIH HHS / United States 75N92019D00031 / HL / NHLBI NIH HHS / United States UL1 TR000040 / TR / NCATS NIH HHS / United States R01 HL151855 / HL / NHLBI NIH HHS / United States HHSN268201800010I / HB / NHLBI NIH HHS / United States UM1 DK078616 / DK / NIDDK NIH HHS / United States 75N92020D00006 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC95166 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States UL1 TR001881 / TR / NCATS NIH HHS / United States HHSN268201800011I / HB / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States R01 HL142809 / HL / NHLBI NIH HHS / United States 75N92021D00004 / WH / WHI NIH HHS / United States |
ePub date:
23/07