Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

CHD Exome+ Consortium, EPIC-InterAct Consortium, Michigan Biobank, Wei Zhao, Asif Rasheed, Emmi Tikkanen, Jung-Jin Lee, Adam S. Butterworth, Joanna M. M. Howson, Themistocles L. Assimes, Rajiv Chowdhury, Marju Orho-Melander, Scott Damrauer, Aeron Small, Senay Asma, Minako Imamura, Toshimasa Yamauch, John C. Chambers, Peng Chen, Bishwa R. SapkotaNabi Shah, Sehrish Jabeen, Praveen Surendran, Yingchang Lu, Weihua Zhang, Atif Imran, Shahid Abbas, Faisal Majeed, Kevin Trindade, Nadeem Qamar, Nadeem Hayyat Mallick, Zia Yaqoob, Tahir Saghir, Syed Nadeem Hasan Rizvi, Anis Memon, Syed Zahed Rasheed, Fazal-Ur-Rehman Memon, Khalid Mehmood, Naveeduddin Ahmed, Irshad Hussain Qureshi, Tanveer-Us-Salam, Wasim Iqbal, Uzma Malik, Narinder Mehra, Jane Z. Kuo, Wayne H-H Sheu, Xiuqing Guo, Chao A. Hsiung, Jyh-Ming J Juang, Kent D. Taylor, Yi-Jen Hung, Wen-Jane Lee, Thomas Quertermous, I.-Te Lee, Chih-Cheng Hsu, Erwin P. Bottinger, Sarju Ralhan, Yik-Ying Teo, Tzung-Dau Wang, Dewan S. Alam, Emanuele Di Angelantonio, Steve Epstein, Sune F. Nielsen, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Robin Young, Marianne Benn, Ruth Frikke-Schmidt, Pia R. Kamstrup, J. Wouter Jukema, Naveed Sattar, Roelof A. J. Smit, Ren-Hua Chung, Kae-Woei Liang, Sonia S. Anand, Dharambir K. Sanghera, Samuli Ripatti, Ruth J. F. Loos, Jaspal S. Kooner, E. Shyong Tai, Jerome I. Rotter, Yii-Der Ida Chen, Philippe Frossard, Shiro Maeda, Takashi Kadowaki, Muredach P. Reilly, Guillaume Paré, Olle Melander, Veikko Salomaa, Daniel J. Rader, John Danesh, Benjamin F. Voight, Danish Saleheen

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

Original languageEnglish
Pages (from-to)1450-1457
Number of pages8
JournalNature Genetics
Volume49
Issue number10
Early online date4 Sep 2017
DOIs
Publication statusPublished - 2017

Keywords

  • Asia/epidemiology
  • Asian Continental Ancestry Group/genetics
  • Biomarkers
  • Comorbidity
  • Coronary Disease/epidemiology
  • Diabetes Mellitus, Type 2/drug therapy
  • Europe/epidemiology
  • European Continental Ancestry Group/genetics
  • Genetic Loci/genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • HLA-DRB5 Chains/genetics
  • Humans
  • Metabolic Networks and Pathways/genetics
  • Metabolic Syndrome/epidemiology
  • Molecular Targeted Therapy
  • Mutation, Missense
  • Polymorphism, Single Nucleotide
  • Risk Factors

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    CHD Exome+ Consortium, EPIC-InterAct Consortium, Michigan Biobank, Zhao, W., Rasheed, A., Tikkanen, E., Lee, J-J., Butterworth, A. S., Howson, J. M. M., Assimes, T. L., Chowdhury, R., Orho-Melander, M., Damrauer, S., Small, A., Asma, S., Imamura, M., Yamauch, T., Chambers, J. C., Chen, P., ... Saleheen, D. (2017). Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nature Genetics, 49(10), 1450-1457. https://doi.org/10.1038/ng.3943