Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study

Title: Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study
Authors: Chambers, JC
Loh, M
Lehne, B
Drong, A
Kriebel, J
Motta, V
Wahl, S
Elliott, HR
Rota, F
Scott, WR
Zhang, W
Tan, S-T
Campanella, G
Chadeau-Hyam, M
Yengo, L
Richmond, RC
Adamowicz-Brice, M
Afzal, U
Bozaoglu, K
Mok, ZY
Ng, HK
Pattou, F
Prokisch, H
Rozario, MA
Tarantini, L
Abbott, J
Ala-Korpela, M
Albetti, B
Ammerpohl, O
Bertazzi, PA
Blancher, C
Caiazzo, R
Danesh, J
Gaunt, TR
De Lusignan, S
Gieger, C
Illig, T
Jha, S
Jones, S
Jowett, J
Kangas, AJ
Kasturiratne, A
Kato, N
Kotea, N
Kowlessur, S
Pitkaeniemi, J
Punjabi, P
Saleheen, D
Schafmayer, C
Soininen, P
Tai, E-S
Thorand, B
Tuomilehto, J
Wickremasinghe, AR
Kyrtopoulos, SA
Aitman, TJ
Herder, C
Hampe, J
Cauchi, S
Relton, CL
Froguel, P
Soong, R
Vineis, P
Jarvelin, M-R
Scott, J
Grallert, H
Bollati, V
Elliott, P
McCarthy, MI
Kooner, JS
Item Type: Journal Article
Abstract: Background Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. Methods We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10−7. We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians. Findings 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8–3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1–2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07–1·11; p=1·3 × 10−17) for ABCG1, 0·94 (0·92–0·95; p=4·2 × 10−11) for PHOSPHO1, 0·94 (0·92–0·96; p=1·4 × 10−9) for SOCS3, 1·07 (1·04–1·09; p=2·1 × 10−10) for SREBF1, and 0·92 (0·90–0·94; p=1·2 × 10−17) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79–4·42; p=1·3 × 10−26), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10−34). Interpretation DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians.
Issue Date: 18-Jun-2015
Date of Acceptance: 18-Jun-2015
ISSN: 2213-8587
Publisher: Elsevier
Start Page: 526
End Page: 534
Journal / Book Title: The Lancet Diabetes & Endocrinology
Volume: 3
Issue: 7
Copyright Statement: © 2015 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Sponsor/Funder: British Heart Foundation
Medical Research Council (MRC)
Wellcome Trust
Medical Research Council (MRC)
National Institute for Health Research
Action on Hearing Loss
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: SP/04/02
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
Asian Continental Ancestry Group
Case-Control Studies
DNA Methylation
Diabetes Mellitus, Type 2
Epigenesis, Genetic
European Continental Ancestry Group
Genetic Markers
Genome-Wide Association Study
Middle Aged
Prospective Studies
Risk Factors
Publication Status: Published
Appears in Collections:Division of Surgery
National Heart and Lung Institute
Department of Medicine
Faculty of Medicine
Faculty of Natural Sciences
Epidemiology, Public Health and Primary Care

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