Browsing by Author "Drong, A."

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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
(The Lancet, Diabetes & Endocrinology, 2015) Chambers, J.C.; Loh, M.; Lehne, B.; Drong, A.; Kriebel, J.; Motta, V.; Wahl, S.; Elliott., H.R; Rota, F.; Scott, W.R.; Zhang, W.; Tan, S.T.; Campanella, G.; Chadeau-Hyam, M.; Yengo, L.; Richmond, R.C.; Adamowicz-Brice, M.; Afzal, U.; Bozaoglu, K.; Mok, Z.Y.; Ng, H.K.; Pattou, F.; Prokisch, H.; Rozario, M.A.; Tarantini, L.; Abbott, J.; Ala-Korpela, M.; Albetti, B.; Ammerpohl, O.; Bertazzi, P.A.; Blancher, C.; Caiazzo, R.; Danesh, J.; Gaunt, T.R.; de Lusignan, S.; Gieger, C.; Illig, T.; Jha, S.; Jones, S.; Jowett, J.; Kangas, A.J.; Kasturiratne, A.; Kato, N.; Kotea, N.; Kowlessur, S.; Pitkäniemi, J.; Punjabi, P.; Saleheen, D.; Schafmayer, C.; Soininen, P.; Tai, E.S.; Thorand, B.; Tuomilehto, J.; Wickremasinghe, A.R.; Kyrtopoulos, S.A.; Aitman, T.J.; Herder, C.; Hampe, J.; Cauchi, S.; Relton, C.L.; Froguel, P.; Soong, R.; Vineis, P.; Jarvelin, M.R.; Scott, J.; Grallert, H.; Bollati, V.; Elliott, P.; McCarthy, M.I.; Kooner, J.S. J
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 glycemic 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 Welcome 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. Copyright © 2015 Elsevier Ltd. All rights reserved.
Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
(Nature Publishing Group, 2017) Whal, S.; Drong, A.; Lehne, B.; Loh, M.; Scott, W.R.; Kunze, S.; Tsai, P.C.; Ried, J.S.; Zhang, W.; Yang, Y.; Tan, S.; Fiorito, G.; Franke, L.; Guarrera, S.; Kasela, S.; Kriebel, J.; Richmond, R.C.; Adamo, M.; Afzal, U.; Ala-Korpela, M.; Albeetti, B.; Ammerpohl, O.; Apperley, J.F.; Beekman, M.; Bertazzi, P.A.; Black, S.L.; Blancher, C.; Bonder, M.J.; Brosch, M.; Carstensen-Kirberg, M.; de Craen, A.J.; de Lusignan, S.; Dehghan, A.; Elkalaawy, M.; Fischer, K.; Franco, O.H.; Gaunt, T.R.; Hampe, J.; Hashemi, M.; Isaacs, A.; Jenkinson, A.; Jha, S.; Kato, N.; Krogh, V.; Laffan, M.; Meisinger, C.; Meitinger, T.; Mok, Z.Y.; Motta, V.; Ng, H.K.; Nikolakopoulou, Z.; Nteliopoulos, G.; Panico, S.; Pervjakova, N.; Prokisch, H.; Rathmann, W.; Roden, M.; Rota, F.; Rozario, M.A.; Sandling, J.K.; Schafmayer, C.; Schramm, K.; Siebert, R.; Slagboom, P.E.; Soininen, P.; Stolk, L.; Strauch, K.; Tai, E.S.; Tarantini, L.; Thorand, B.; Tigchelaar, E.F.; Tumino, R.; Uitterlinden, A.G.; van Duijn, C.; van Meurs, J.B.; Vineis, P.; Wickremasinghe, A.R.; Wijmenga, C.; Yang, T.P.; Yuan, W.; Zhernakova, A.; Batterham, R.L.; Smith, G.D.; Deloukas, P.; Heijmans, B.T.; Herder, C.; Hofman, A.; Lindgren, C.M.; Milani, L.; van der Harst, P.; Peters, A.; Illig, T.; Relton, C.L.; Waldenberger, M.; Järvelin, M.R.; Bollati, V.; Soong, R.; Spector, T.D.; Scott, J.; McCarthy, M.I.; Elliott, P.; Bell, J.T.; Matullo, G.; Gieger, C.; Kooner, J.S.; Grallert, H.; Chambers, J.C.
Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.