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Lancet Diabetes Endocrinol. 2015 Jul;3(7):526-34. doi: 10.1016/S2213-8587(15)00127-8. Epub 2015 Jun 18.

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.

Author information

1
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; MRC-PHE Centre for Environment and Health, Imperial College London, London, UK; Ealing Hospital NHS Trust, Middlesex, UK; Imperial College Healthcare NHS Trust, London, UK. Electronic address: john.chambers@ic.ac.uk.
2
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Institute of Health Sciences, University of Oulu, Oulu, Finland.
3
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
5
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Munich, Germany.
6
Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
7
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; MRC-PHE Centre for Environment and Health, Imperial College London, London, UK; MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
8
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; National Heart and Lung Institute, Imperial College London, London, UK.
9
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Ealing Hospital NHS Trust, Middlesex, UK.
10
National Heart and Lung Institute, Imperial College London, London, UK; Ealing Hospital NHS Trust, Middlesex, UK.
11
European Genomic Institute for Diabetes, Lille, France; CNRS UMR8199, Pasteur Institute of Lille, Lille, France; Lille 2 University, Lille, France.
12
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
13
Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, UK.
14
Genomics and Systems Biology, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
15
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
16
European Genomic Institute for Diabetes, Lille, France; Lille 2 University, Lille, France; Inserm UMR859, Claude-Huriez Hospital, Lille, France.
17
Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, München, Germany.
18
Bioinformatics Support Service, Imperial College London, London, UK.
19
Computational Medicine, University of Bristol, Bristol, UK; Computational Medicine, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Oulu University Hospital, Oulu, Finland.
20
Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel Campus, Kiel, Germany.
21
High Throughput Genomics, Oxford Genomic Centre, University of Oxford, Oxford, UK.
22
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK; European Genomic Institute for Diabetes, Lille, France; Genomics and Systems Biology, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
23
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
24
University of Surrey, Guildford, UK.
25
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
26
Hannover Medical School, Hannover Unified Biobank, Hannover, Germany.
27
Department of Endocrinology, Diabetes and Obesity, Max Healthcare, New Delhi, India.
28
Computational Medicine, University of Oulu, Oulu, Finland.
29
Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
30
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
31
Department of Health Sciences, University of Mauritius, Reduit, Mauritius.
32
Ministry of Health and Quality of Life, Port louis, Mauritius.
33
Hjelt Institute, School of Medicine, University of Helsinki, Finland; Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.
34
Imperial College Healthcare NHS Trust, London, UK.
35
Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Public Health and Primary Care, University of Cambridge Strangeways Research Laboratory, Cambridge, UK; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
36
Department of Visceral and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel Campus, Kiel, Germany.
37
Computational Medicine, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
38
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Duke National University of Singapore Graduate Medical School, Singapore, Singapore.
39
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Munich, Germany.
40
Department of Public Health, University of Helsinki, Finland.
41
National Hellenic Research Foundation, Institute of Biology, Pharmaceutical Chemistry and Biotechnology, Athens, Greece.
42
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Düsseldorf, Germany.
43
Medical Department 1, University Hospital of the Technical University Dresden, Dresden, Germany.
44
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; European Genomic Institute for Diabetes, Lille, France; CNRS UMR8199, Pasteur Institute of Lille, Lille, France; Lille 2 University, Lille, France.
45
Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pathology, National University Hospital, Singapore, Singapore.
46
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; HuGeF Foundation, Torino, Italy.
47
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; MRC-PHE Centre for Environment and Health, Imperial College London, London, UK; Institute of Health Sciences, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Unit of Primary Care, Oulu, Finland.
48
National Heart and Lung Institute, Imperial College London, London, UK.
49
Department of Epidemiology and Biostatistics, Imperial College London, London, UK; MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
50
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK; Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.
51
MRC-PHE Centre for Environment and Health, Imperial College London, London, UK; National Heart and Lung Institute, Imperial College London, London, UK; Ealing Hospital NHS Trust, Middlesex, UK; Imperial College Healthcare NHS Trust, London, UK. Electronic address: j.kooner@ic.ac.uk.

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.

FUNDING:

The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.

PMID:
26095709
PMCID:
PMC4724884
DOI:
10.1016/S2213-8587(15)00127-8
[Indexed for MEDLINE]
Free PMC Article
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