Article | Published:

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

Nature Genetics volume 49, pages 14501457 (2017) | Download Citation

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.

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Acknowledgements

D.S. has received support from NHLBI, NINDS, Pfizer, Regeneron Pharmaceuticals, Genentech, and Eli Lilly. Genotyping in PROMIS was funded by the Wellcome Trust, UK, and Pfizer. Biomarker assays in PROMIS have been funded through grants awarded by the NIH (RC2HL101834 and RC1TW008485) and Fogarty International (RC1TW008485). The RACE study has been funded by NINDS (R21NS064908), Fogarty International (R21NS064908), and the Center for Non-Communicable Diseases (Karachi, Pakistan). B.F.V. was supported by funding from the American Heart Association (13SDG14330006), the W.W. Smith Charitable Trust (H1201), and the NIH/NIDDK (R01DK101478). J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. V.S. was supported by the Finnish Foundation for Cardiovascular Research. S. Ripatti was supported by the Academy of Finland (251217 and 255847), the Center of Excellence in Complex Disease Genetics, the European Union's Seventh Framework Programme projects ENGAGE (201413) and BioSHaRE (261433), the Finnish Foundation for Cardiovascular Research, Biocentrum Helsinki, and the Sigrid Juselius Foundation. The Mount Sinai IPM Biobank Program is supported by the Andrea and Charles Bronfman Philanthropies. S. Anand is supported by grants from the Canada Research Chair in Ethnic Diversity and CVD and from the Heart and Stroke Michael G. DeGroote Chair in Population Health, McMaster University. Data contributed by Biobank Japan were partly supported by a grant from the Leading Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank the participants and staff of the Copenhagen Ischemic Heart Disease Study and the Copenhagen General Population Study for their important contributions. The CHD Exome+ Consortium was funded by the UK Medical Research Council (G0800270), the British Heart Foundation (SP/09/002), the UK NIHR Cambridge Biomedical Research Centre, the European Research Council (268834), the European Commission's Framework Programme 7 (HEALTH-F2-2012-279233), Merck, and Pfizer. PROSPER has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F2-2009-223004.

Author information

Author notes

    • Wei Zhao
    • , Asif Rasheed
    •  & Emmi Tikkanen

    These authors contributed equally to this work.

    • Benjamin F Voight
    •  & Danish Saleheen

    These authors jointly directed this work.

Affiliations

  1. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Wei Zhao
    •  & Danish Saleheen
  2. Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Wei Zhao
    • , Jung-Jin Lee
    • , Kevin Trindade
    • , Daniel J Rader
    •  & Danish Saleheen
  3. Center for Non-Communicable Diseases, Karachi, Pakistan.

    • Asif Rasheed
    • , Nabi Shah
    • , Sehrish Jabeen
    • , Atif Imran
    • , Faisal Majeed
    • , Philippe Frossard
    •  & Danish Saleheen
  4. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Emmi Tikkanen
    •  & Samuli Ripatti
  5. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Emmi Tikkanen
    •  & Samuli Ripatti
  6. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Adam S Butterworth
    • , Joanna M M Howson
    • , Rajiv Chowdhury
    • , Praveen Surendran
    • , Emanuele Di Angelantonio
    • , Robin Young
    •  & John Danesh
  7. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Themistocles L Assimes
    •  & Thomas Quertermous
  8. Department of Clinical Sciences, Lund University, Malmö, Sweden.

    • Marju Orho-Melander
    •  & Olle Melander
  9. Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Scott Damrauer
  10. Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Aeron Small
    • , Daniel J Rader
    •  & Benjamin F Voight
  11. Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada.

    • Senay Asma
  12. Laboratory for Endocrinology, Metabolism, and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Minako Imamura
    •  & Shiro Maeda
  13. Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

    • Minako Imamura
    •  & Shiro Maeda
  14. Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan.

    • Minako Imamura
    •  & Shiro Maeda
  15. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

    • Toshimasa Yamauch
    •  & Takashi Kadowaki
  16. Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

    • John C Chambers
    • , Weihua Zhang
    •  & Jaspal S Kooner
  17. Ealing Hospital NHS Trust, Southall, UK.

    • John C Chambers
    •  & Weihua Zhang
  18. Imperial College Healthcare NHS Trust, London, UK.

    • John C Chambers
    •  & Jaspal S Kooner
  19. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.

    • Peng Chen
    •  & Yik Ying Teo
  20. Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Bishwa R Sapkota
    •  & Dharambir K Sanghera
  21. Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan.

    • Nabi Shah
  22. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Yingchang Lu
    • , Erwin P Bottinger
    •  & Ruth J F Loos
  23. Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Yingchang Lu
    •  & Ruth J F Loos
  24. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Yingchang Lu
    •  & Ruth J F Loos
  25. Faisalabad Institute of Cardiology, Faisalabad, Pakistan.

    • Shahid Abbas
  26. National Institute of Cardiovascular Disorders, Karachi, Pakistan.

    • Nadeem Qamar
    • , Zia Yaqoob
    • , Tahir Saghir
    • , Syed Nadeem Hasan Rizvi
    •  & Anis Memon
  27. Punjab Institute of Cardiology, Lahore, Pakistan.

    • Nadeem Hayyat Mallick
  28. Karachi Institute of Heart Diseases, Karachi, Pakistan.

    • Syed Zahed Rasheed
  29. Red Crescent Institute of Cardiology, Hyderabad, Pakistan.

    • Fazal-ur-Rehman Memon
  30. Department of Medicine, Civil Hospital, Karachi, Pakistan.

    • Khalid Mehmood
  31. Department of Neurology, Liaquat National Hospital, Karachi, Pakistan.

    • Naveeduddin Ahmed
  32. Department of Medicine, Mayo Hospital and King Edward Medical University, Lahore, Pakistan.

    • Irshad Hussain Qureshi
    •  & Uzma Malik
  33. Department of Neurology, Lahore General Hospital, Lahore, Pakistan.

    • Tanveer-us-Salam
    •  & Wasim Iqbal
  34. All-India Institute of Medical Sciences, New Delhi, India.

    • Narinder Mehra
  35. Clinical and Medical Affairs, CardioDx, Inc., Redwood City, California, USA.

    • Jane Z Kuo
  36. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.

    • Jane Z Kuo
    • , Xiuqing Guo
    • , Kent D Taylor
    • , Jerome I Rotter
    •  & Yii-Der Ida Chen
  37. Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.

    • Wayne H-H Sheu
    •  & I-Te Lee
  38. School of Medicine, National Yang-Ming University, Taipei, Taiwan, and Chung Shan Medical University, Taichung, Taiwan.

    • Wayne H-H Sheu
    •  & I-Te Lee
  39. Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.

    • Chao A Hsiung
    • , Chih-Cheng Hsu
    •  & Ren-Hua Chung
  40. Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

    • Jyh-Ming J Juang
    •  & Tzung-Dau Wang
  41. Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

    • Yi-Jen Hung
  42. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.

    • Wen-Jane Lee
  43. Hero DMC Heart Institute Ludhiana, Punjab, India.

    • Sarju Ralhan
  44. Genome Institute of Singapore, A*STAR, Singapore.

    • Yik Ying Teo
  45. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

    • Yik Ying Teo
  46. National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.

    • Yik Ying Teo
  47. Life Sciences Institute, National University of Singapore, Singapore.

    • Yik Ying Teo
  48. International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.

    • Dewan S Alam
  49. MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA.

    • Steve Epstein
  50. Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, Denmark.

    • Sune F Nielsen
  51. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Børge G Nordestgaard
    • , Anne Tybjaerg-Hansen
    •  & Pia R Kamstrup
  52. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Børge G Nordestgaard
  53. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • Anne Tybjaerg-Hansen
    •  & Ruth Frikke-Schmidt
  54. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.

    • Marianne Benn
    •  & J Wouter Jukema
  55. Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.

    • J Wouter Jukema
  56. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

    • Naveed Sattar
  57. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

    • Roelof Smit
  58. Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.

    • Kae-Woei Liang
  59. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.

    • Sonia Anand
  60. Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Dharambir K Sanghera
  61. Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA.

    • Dharambir K Sanghera
  62. National Institute for Health and Welfare, Helsinki, Finland.

    • Samuli Ripatti
    •  & Veikko Salomaa
  63. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Samuli Ripatti
  64. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • E Shyong Tai
  65. Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University, New York, New York, USA.

    • Muredach Reilly
  66. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

    • Guillaume Pare
  67. Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden.

    • Olle Melander
  68. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • John Danesh
  69. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.

    • John Danesh
  70. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Benjamin F Voight
  71. Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Benjamin F Voight

Consortia

  1. CHD Exome+ Consortium

  2. EPIC-CVD Consortium

  3. EPIC-Interact Consortium

  4. Michigan Biobank

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Contributions

A.R., B.F.V., B.G.N., D.J.R., D.S., D.S.A., J.I.R., M.R., O.M., P.F., R.C., R.J.F.L., S. Anand, S.E., S.M., S. Ripatti, T.-D.W., W.H.-H.S., and W. Zhao conceived of and designed the experiments. A.I., A.M., A.R., A.S.B., B.F.V., B.G.N., B.R.S., C.A.H., D.J.R., D.K.S., D.S., D.S.A., E.P.B., E.S.T., E.T., F.M., F.-u.-R.M., G.P., I.-T.L., I.H.Q., J.-J.L., J.C.C., J.I.R., J.M.M.H., J.S.K., J.W.J., J.Z.K., K.-W.L., K.D.T., K.M., K.T., M.B., N.M., M.O.-M., N.A., N.H.M., S.N.H.R., N.Q., N. Sattar, O.M., P.C., P.F., P.S., R.-H.C., R.C., R.F.-S., R.J.F.L., S. Abbas, S. Anand, S.E., S.J., S.M., S.N.H.R., S. Ralhan, S. Ripatti, S.Z.R., T.-D.W., T.-u.S., T.K., T.L.A., T.S., T.Y., U.M., W.H.-H.S., W.I., W. Zhang, W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., Y.Y.T., and Z.Y. performed the experiments. A.R., A.S.B., B.F.V., C.A.H., D.S., E.D.A., E.P.B., E.T., I.-T.L., J.-J.L., J.-M.J.J., J.C.C., J.D., J.M.M.H., J.S.K., J.W.J., J.Z.K., K.-W.L., K.D.T., M.B., M.I., M.O.-M., M.R., N.K.M., N. Sattar, N. Shah, O.M., P.C., P.F., P.R.K., P.S., R.-H.C., R.C., R.F.-S., R.J.F.L., R.S., R.Y., S. Anand, S. Asma, S.D., S.F.N., S.M., S. Ralhan, T.-D.W., N.M., T.L.A., T.Q., T.S., T.Y., U.M., V.S., W.-J.L., W.H.-H.S., W. Zhang, W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., and Y.Y.T. performed statistical analyses. A.I., A.R., A.S., A.S.B., A.T.-H., B.F.V., B.R.S., C.-C.H., C.A.H., D.K.S., D.S., E.D.A., E.P.B., E.S.T., E.T., F.M., G.P., I.-T.L., J.-J.L., J.-M.J.J., J.C.C., J.D., J.I.R., J.S.K., J.Z.K., K.-W.L., K.D.T., K.T., M.I., M.O.-M., M.R., N.H.M., N.Q., N. Sattar, N. Shah, O.M., P.C., P.R.K., P.S., R.-H.C., R.F.-S., R.J.F.L., R.S., R.Y., S. Abbas, S. Asma, S.D., S.J., S. Ralhan, T.K., T.L.A., T.Q., T.S., T.Y., U.M., V.S., W.-J.L., W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., Y.Y.T., and Z.Y. analyzed the data. A.M., A.S., A.T.-H., B.F.V., B.G.N., D.J.R., D.S., F.u.R.M., G.P., I.H.Q., J.-M.J.J., J.D., J.W.J., N.M., K.M., M.B., M.R., N.A., P.R.K., R.S., S.E., S.N.H.R., S. Ripatti, S.Z.R., T.-u.-S., V.S., W.I., and W. Zhao contributed-reagents, materials, and/or analysis tools. A.R., A.S.B., B.F.V., D.J.R., D.K.S., D.S., E.T., G.P., J.-J.L., J.D., J.I.R., J.M.M.H., M.R., N. Sattar, V.S., and W. Zhao wrote the manuscript. D.S. and B.F.V. led the writing group. W. Zhao, A.R., E.T., B.F.V., and D.S. were equal contributors. B.F.V. and D.S. jointly supervised all aspects of the work.

Competing interests

The authors declare competing financial interests from their affiliations with Pfizer, Regeneron Pharmaceuticals, Genenetech, and Eli Lilly.

Corresponding authors

Correspondence to Benjamin F Voight or Danish Saleheen.

Supplementary information

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About this article

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DOI

https://doi.org/10.1038/ng.3943

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