Browsing by Author "Ng, H.K."

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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.
Identification of genetic effects underlying type 2 diabetes in South Asian and European populations
(Nature Publishing Group UK, 2022) Loh, M.; Zhang, W.; Ng, H.K.; Schmid, K.; Lamri, A.; Tong, L.; Ahmad, M.; Lee, J.J.; Ng, M.C.Y.; Petty, L.E.; Spracklen, C.N.; Takeuchi, F.; Islam, M.T.; Jasmine, F.; Kasturiratne, A.; Kibriya, M.; Mohlke, K.L.; Paré, G.; Prasad, G.; Shahriar, M.; Chee, M.L.; de Silva, H.J.; Engert, J.C.; Gerstein, H.C.; Mani, K.R.; Sabanayagam, C.; Vujkovic, M.; Wickremasinghe, A.R.; Wong, T.Y.; Yajnik, C.S.; Yusuf, S.; Ahsan, H.; Bharadwaj, D.; Anand, S.S.; Below, J.E.; Boehnke, M.; Bowden, D.W.; Chandak, G.R.; Cheng, C.Y.; Kato, N.; Mahajan, A.; Sim, X.; McCarthy, M.I.; Morris, A.P.; Kooner, J.S.; Saleheen, D.; Chambers, J.C.
South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.
Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
(Nature Publishing Company, 2015) Kato, N.; Loh, M.; Takeuchi, F.; Verweij, N.; Wang, X.; Zhang, W.; Kelly, T.N.; Saleheen, D.; Lehne, B.; Leach, I.M.; Drong, A.W.; Abbott, J.; Wahl, S.; Tan, S.T.; Scott, W.R.; Campanella, G.; Chadeau-Hyam, M.; Afzal, U.; Ahluwalia, T.S.; Bonder, M.J.; Chen, P.; Dehghan, A.; Edwards, T.L.; Esko, T.; Go, M.J.; Harris, S.E.; Hartiala, J.; Kasela, S.; Kasturiratne, A.; Khor, C.C.; Kleber, M.E.; Li, H.; Mok, Z.Y.; Nakatochi, M.; Sapari, N.S.; Saxena, R.; Stewart, A.F.; Stolk, L.; Tabara, Y.; Teh, A.L.; Wu, Y.; Wu, J.Y.; Zhang, Y.; Aits, I.; Da Silva Couto Alves, A.; Das, S.; Dorajoo, R.; Hopewell, J.C.; Kim, Y.K.; Koivula, R.W.; Luan, J.; Lyytikäinen, L.P.; Nguyen, Q.N.; Pereira, M.A.; Postmus, I.; Raitakari, O.T.; Bryan, M.S.; Scott, R.A.; Sorice, R.; Tragante, V.; Traglia, M.; White, J.; Yamamoto, K.; Zhang, Y.; Adair, L.S.; Ahmed, A.; Akiyama, K.; Asif, R.; Aung, T.; Barroso, I.; Bjonnes, A.; Braun, T.R.; Cai, H.; Chang, L.C.; Chen, C.H.; Cheng, C.Y.; Chong, Y.S.; Collins, R.; Courtney, R.; Davies, G.; Delgado, G.; Do, L.D.; Doevendans, P.A.; Gansevoort, R.T.; Gao, Y.T.; Grammer, T.B.; Grarup, N.; Grewal, J.; Gu, D.; Wander, G.S.; Hartikainen, A.L.; Hazen, S.L.; He, J.; Heng, C.K.; Hixson, J.E.; Hofman, A.; Hsu, C.; Huang, W.; Husemoen, L.L.; Hwang, J.Y.; Ichihara, S.; Igase, M.; Isono, M.; Justesen, J.M.; Katsuya, T.; Kibriya, M.G.; Kim, Y.J.; Kishimoto, M.; Koh, W.P.; Kohara, K.; Kumari, M.; Kwek, K.; Lee, N.R.; Lee, J.; Liao, J.; Lieb, W.; Liewald, D.C.; Matsubara, T.; Matsushita, Y.; Meitinger, T.; Mihailov, E.; Milani, L.; Mills, R.; Mononen, N.; Müller-Nurasyid, M.; Nabika, T.; Nakashima, E.; Ng, H.K.; Nikus, K.; Nutile, T.; Ohkubo, T.; Ohnaka, K.; Parish, S.; Paternoster, L.; Peng, H.; Peters, A.; Pham, S.T.; Pinidiyapathirage, M.J.; Rahman, M.; Rakugi, H.; Rolandsson, O.; Rozario, M.A.; Ruggiero, D.; Sala, C.F.; Sarju, R.; Shimokawa, K.; Snieder, H.; Sparso, T.; Spiering, W.; Starr, J.M.; Stott, D.J.; Stram, D.O.; Sugiyama, T.; Szymczak, S.; Tang, W.H.; Tong, L.; Trompet, S.; Turjanmaa, V.; Ueshima, H.; Uitterlinden, A.G.; Umemura, S.; Vaarasmaki, M.; van Dam, R.M.; van Gilst, W.H.; van Veldhuisen, D.J.; Viikari, J.S.; Waldenberger, M.; Wang, Y.; Wang, A.; Wilson, R.; Wong, T.Y.; Xiang, Y.B.; Yamaguchi, S.; Ye, X.; Young, R.D.; Young, T.L.; Yuan, J.M.; Zhou, X.; Asselbergs, F.W.; Ciullo, M.; Clarke, R.; Deloukas, P.; Franke, A.; Franks, P.W.; Franks, S.; Friedlander, Y.; Gross, M.D.; Guo, Z.; Hansen, T.; Jarvelin, M.R.; Jorgensen, T.; Jukema, J.W.; Kähönen, M.; Kajio, H.; Kivimaki, M.; Lee, J.Y.; Lehtimäki, T.; Linneberg, A.; Miki, T.; Pedersen, O.; Samani, N.J.; Sorensen, T.I.; Takayanagi, R.; Toniolo, D.; BIOS-consortium; CARDIo GRAMplusCD; LifeLines Cohort Study; InterAct Consortium; Ahsan, H.; Allayee, H.; Chen, Y.T.; Danesh, J.; Deary, I.J.; Franco, O.H.; Franke, L.; Heijman, B.T.; Holbrook, J.D.; Isaacs, A.; Kim, B.J.; Lin, X.; Liu, J.; März, W.; Metspalu, A.; Mohlke, K.L.; Sanghera, D.K.; Shu, X.O.; van Meurs, J.B.; Vithana, E.; Wickremasinghe, A.R.; Wijmenga, C.; Wolffenbuttel, B.H.; Yokota, M.; Zheng, W.; Zhu, D.; Vineis, P.; Kyrtopoulos, S.A.; Kleinjans, J.C.; McCarthy, M.I.; Soong, R.; Gieger, C.; Scott, J.; Teo, Y.Y.; He, J.; Elliott, P.; Tai, E.S.; van der Harst, P.; Kooner, J.S.; Chambers, J.C.
We carried out a trans-ancestry genome-wide association and replication study of blood pressurephenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNAmethylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNAmethylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.