| Title: |
Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis |
| Authors: |
Wheeler, E; Leong, A; Liu, C-T; Hivert, M-F; Strawbridge, RJ; Podmore, C; Li, M; Yao, J; Sim, X; Hong, J; Chu, AY; Zhang, W; Wang, X; Chen, P; Maruthur, NM; Porneala, BC; Sharp, SJ; Jia, Y; Kabagambe, EK; Chang, L-C; Chen, W-M; Elks, CE; Evans, DS; Fan, Q; Giulianini, F; Go, MJ; Hottenga, J-J; Hu, Y; Jackson, AU; Kanoni, S; Kim, YJ; Kleber, ME; Ladenvall, C; Lecoeur, C; Lim, S-H; Lu, Y; Mahajan, A; Marzi, C; Nalls, MA; Navarro, P; Nolte, IM; Rose, LM; Rybin, DV; Sanna, S; Shi, Y; Stram, DO; Takeuchi, F; Tan, SP; van der Most, PJ; Van Vliet-Ostaptchouk, JV; Wong, A; Yengo, L; Zhao, W; Goel, A; Martinez Larrad, MT; Radke, D; Salo, P; Tanaka, T; van Iperen, EPA; Abecasis, G; Afaq, S; Alizadeh, BZ; Bertoni, AG; Bonnefond, A; Böttcher, Y; Bottinger, EP; Campbell, H; Carlson, OD; Chen, C-H; Cho, YS; Garvey, WT; Gieger, C; Goodarzi, MO; Grallert, H; Hamsten, A; Hartman, CA; Herder, C; Hsiung, CA; Huang, J; Igase, M; Isono, M; Katsuya, T; Khor, C-C; Kiess, W; Kohara, K; Kovacs, P; Lee, J; Lee, W-J; Lehne, B; Li, H; Liu, J; Lobbens, S; Luan, J; Lyssenko, V; Meitinger, T; Miki, T; Miljkovic, I; Moon, S; Mulas, A; Müller, G; Müller-Nurasyid, M; Nagaraja, R; Nauck, M; Pankow, JS; Polasek, O; Prokopenko, I; Ramos, PS; Rasmussen-Torvik, L; Rathmann, W; Rich, SS; Robertson, NR; Roden, M; Roussel, R; Rudan, I; Scott, RA; Scott, WR; Sennblad, B; Siscovick, DS; Strauch, K; Sun, L; Swertz, M; Tajuddin, SM; Taylor, KD; Teo, Y-Y; Tham, YC; Tönjes, A; Wareham, NJ; Willemsen, G; Wilsgaard, T; Hingorani, AD; EPIC-CVD Consortium; EPIC-InterAct Consortium; Lifelines Cohort Study; Egan, J; Ferrucci, L; Hovingh, GK; Jula, A; Kivimaki, M; Kumari, M; Njølstad, I; Palmer, CNA; Serrano Ríos, M; Stumvoll, M; Watkins, H; Aung, T; Blüher, M; Boehnke, M; Boomsma, DI; Bornstein, SR; Chambers, JC; Chasman, DI; Chen, Y-DI; Chen, Y-T; Cheng, C-Y; Cucca, F; de Geus, EJC; Deloukas, P; Evans, MK; Fornage, M; Friedlander, Y; Froguel, P; Groop, L; Gross, MD; Harris, TB; Hayward, C; Heng, C-K; Ingelsson, E; Kato, N; Kim, B-J; Koh, W-P; Kooner, JS; Körner, A; Kuh, D; Kuusisto, J; Laakso, M; Lin, X; Liu, Y; Loos, RJF; Magnusson, PKE; März, W; McCarthy, MI; Oldehinkel, AJ; Ong, KK; Pedersen, NL; Pereira, MA; Peters, A; Ridker, PM; Sabanayagam, C; Sale, M; Saleheen, D; Saltevo, J; Schwarz, PE; Sheu, WHH; Snieder, H; Spector, TD; Tabara, Y; Tuomilehto, J; van Dam, RM; Wilson, JG; Wilson, JF; Wolffenbuttel, BHR; Wong, TY; Wu, J-Y; Yuan, J-M; Zonderman, AB; Soranzo, N; Guo, X; Roberts, DJ; Florez, JC; Sladek, R; Dupuis, J; Morris, AP; Tai, E-S; Selvin, E; Rotter, JI; Langenberg, C; Barroso, I; Meigs, JB |
| Publisher Information: |
Public Library of Science (PLoS); //doi.org/10.1371/journal.pmed.1002383 |
| Publication Year: |
2017 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Diabetes Mellitus; Type 2; genetic variation; Genome-Wide Association Study; Hemoglobin A; Glycosylated; humans; phenotype; risk |
| Description: |
BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/267684 |
| DOI: |
10.17863/CAM.13618 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/267684; https://doi.org/10.17863/CAM.13618 |
| Rights: |
CC0 1.0 Universal (CC0 1.0) Public Domain Dedication ; https://creativecommons.org/publicdomain/zero/1.0/ |
| Accession Number: |
edsbas.C9CB9576 |
| Database: |
BASE |