Comparative Study

. 2017 Oct;49(10):1450-1457.

doi: 10.1038/ng.3943. Epub 2017 Sep 4.

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

Wei Zhao^{1

2}, Asif Rasheed³, Emmi Tikkanen^{4

5}, Jung-Jin Lee², Adam S Butterworth⁶, Joanna M M Howson⁶, Themistocles L Assimes⁷, Rajiv Chowdhury⁶, Marju Orho-Melander⁸, Scott Damrauer⁹, Aeron Small¹⁰, Senay Asma¹¹, Minako Imamura^{12

13

14}, Toshimasa Yamauch¹⁵, John C Chambers^{16

17

18}, Peng Chen¹⁹, Bishwa R Sapkota²⁰, Nabi Shah^{3

21}, Sehrish Jabeen³, Praveen Surendran⁶, Yingchang Lu^{22

23

24}, Weihua Zhang^{16

17}, Atif Imran³, Shahid Abbas²⁵, Faisal Majeed³, Kevin Trindade², Nadeem Qamar²⁶, Nadeem Hayyat Mallick²⁷, Zia Yaqoob²⁶, Tahir Saghir²⁶, Syed Nadeem Hasan Rizvi²⁶, Anis Memon²⁶, Syed Zahed Rasheed²⁸, Fazal-Ur-Rehman Memon²⁹, Khalid Mehmood³⁰, Naveeduddin Ahmed³¹, Irshad Hussain Qureshi³², Tanveer-Us-Salam³³, Wasim Iqbal³³, Uzma Malik³², Narinder Mehra³⁴, Jane Z Kuo^{35

36}, Wayne H-H Sheu^{37

38}, Xiuqing Guo³⁶, Chao A Hsiung³⁹, Jyh-Ming J Juang⁴⁰, Kent D Taylor³⁶, Yi-Jen Hung⁴¹, Wen-Jane Lee⁴², Thomas Quertermous⁷, I-Te Lee^{37

38}, Chih-Cheng Hsu³⁹, Erwin P Bottinger²², Sarju Ralhan⁴³, Yik Ying Teo^{19

44

45

46

47}, Tzung-Dau Wang⁴⁰, Dewan S Alam⁴⁸, Emanuele Di Angelantonio⁶, Steve Epstein⁴⁹, Sune F Nielsen⁵⁰, Børge G Nordestgaard^{51

52}, Anne Tybjaerg-Hansen^{51

53}, Robin Young⁶; CHD Exome+ Consortium; Marianne Benn⁵⁴, Ruth Frikke-Schmidt⁵³, Pia R Kamstrup⁵¹; EPIC-CVD Consortium; EPIC-Interact Consortium; Michigan Biobank; J Wouter Jukema^{54

55}, Naveed Sattar⁵⁶, Roelof Smit⁵⁷, Ren-Hua Chung³⁹, Kae-Woei Liang⁵⁸, Sonia Anand⁵⁹, Dharambir K Sanghera^{20

60

61}, Samuli Ripatti^{4

5

62

63}, Ruth J F Loos^{22

23

24}, Jaspal S Kooner^{16

18}, E Shyong Tai⁶⁴, Jerome I Rotter³⁶, Yii-Der Ida Chen³⁶, Philippe Frossard³, Shiro Maeda^{12

13

14}, Takashi Kadowaki¹⁵, Muredach Reilly⁶⁵, Guillaume Pare⁶⁶, Olle Melander^{8

67}, Veikko Salomaa⁶², Daniel J Rader^{2

10}, John Danesh^{6

68

69}, Benjamin F Voight^{10

70

71}, Danish Saleheen^{1

2

3}

Affiliations

¹ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Center for Non-Communicable Diseases, Karachi, Pakistan.
⁴ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁵ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁶ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
⁸ Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁹ Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹¹ Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada.
¹² Laboratory for Endocrinology, Metabolism, and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹³ Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
¹⁴ Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan.
¹⁵ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
¹⁶ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹⁷ Ealing Hospital NHS Trust, Southall, UK.
¹⁸ Imperial College Healthcare NHS Trust, London, UK.
¹⁹ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
²⁰ Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
²¹ Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
²² Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²³ Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁴ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
²⁵ Faisalabad Institute of Cardiology, Faisalabad, Pakistan.
²⁶ National Institute of Cardiovascular Disorders, Karachi, Pakistan.
²⁷ Punjab Institute of Cardiology, Lahore, Pakistan.
²⁸ Karachi Institute of Heart Diseases, Karachi, Pakistan.
²⁹ Red Crescent Institute of Cardiology, Hyderabad, Pakistan.
³⁰ Department of Medicine, Civil Hospital, Karachi, Pakistan.
³¹ Department of Neurology, Liaquat National Hospital, Karachi, Pakistan.
³² Department of Medicine, Mayo Hospital and King Edward Medical University, Lahore, Pakistan.
³³ Department of Neurology, Lahore General Hospital, Lahore, Pakistan.
³⁴ All-India Institute of Medical Sciences, New Delhi, India.
³⁵ Clinical and Medical Affairs, CardioDx, Inc., Redwood City, California, USA.
³⁶ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
³⁷ Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
³⁸ School of Medicine, National Yang-Ming University, Taipei, Taiwan, and Chung Shan Medical University, Taichung, Taiwan.
³⁹ Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
⁴⁰ Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
⁴¹ Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁴² Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
⁴³ Hero DMC Heart Institute Ludhiana, Punjab, India.
⁴⁴ Genome Institute of Singapore, A*STAR, Singapore.
⁴⁵ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
⁴⁶ National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.
⁴⁷ Life Sciences Institute, National University of Singapore, Singapore.
⁴⁸ International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
⁴⁹ MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA.
⁵⁰ Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, Denmark.
⁵¹ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁵² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵³ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁵⁴ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
⁵⁵ Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
⁵⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁵⁷ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁵⁸ Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.
⁵⁹ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
⁶⁰ Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
⁶¹ Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA.
⁶² National Institute for Health and Welfare, Helsinki, Finland.
⁶³ Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁶⁴ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁶⁵ Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University, New York, New York, USA.
⁶⁶ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
⁶⁷ Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁶⁸ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁶⁹ NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
⁷⁰ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷¹ Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 28869590
PMCID: PMC5844224
DOI: 10.1038/ng.3943

Comparative Study

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

Wei Zhao et al. Nat Genet. 2017 Oct.

. 2017 Oct;49(10):1450-1457.

doi: 10.1038/ng.3943. Epub 2017 Sep 4.

Authors

Affiliations

¹ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Center for Non-Communicable Diseases, Karachi, Pakistan.
⁴ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁵ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁶ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
⁸ Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁹ Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹¹ Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada.
¹² Laboratory for Endocrinology, Metabolism, and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹³ Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
¹⁴ Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan.
¹⁵ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
¹⁶ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹⁷ Ealing Hospital NHS Trust, Southall, UK.
¹⁸ Imperial College Healthcare NHS Trust, London, UK.
¹⁹ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
²⁰ Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
²¹ Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
²² Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²³ Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁴ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
²⁵ Faisalabad Institute of Cardiology, Faisalabad, Pakistan.
²⁶ National Institute of Cardiovascular Disorders, Karachi, Pakistan.
²⁷ Punjab Institute of Cardiology, Lahore, Pakistan.
²⁸ Karachi Institute of Heart Diseases, Karachi, Pakistan.
²⁹ Red Crescent Institute of Cardiology, Hyderabad, Pakistan.
³⁰ Department of Medicine, Civil Hospital, Karachi, Pakistan.
³¹ Department of Neurology, Liaquat National Hospital, Karachi, Pakistan.
³² Department of Medicine, Mayo Hospital and King Edward Medical University, Lahore, Pakistan.
³³ Department of Neurology, Lahore General Hospital, Lahore, Pakistan.
³⁴ All-India Institute of Medical Sciences, New Delhi, India.
³⁵ Clinical and Medical Affairs, CardioDx, Inc., Redwood City, California, USA.
³⁶ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
³⁷ Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
³⁸ School of Medicine, National Yang-Ming University, Taipei, Taiwan, and Chung Shan Medical University, Taichung, Taiwan.
³⁹ Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
⁴⁰ Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
⁴¹ Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁴² Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
⁴³ Hero DMC Heart Institute Ludhiana, Punjab, India.
⁴⁴ Genome Institute of Singapore, A*STAR, Singapore.
⁴⁵ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
⁴⁶ National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.
⁴⁷ Life Sciences Institute, National University of Singapore, Singapore.
⁴⁸ International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
⁴⁹ MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA.
⁵⁰ Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, Denmark.
⁵¹ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁵² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵³ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁵⁴ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
⁵⁵ Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
⁵⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁵⁷ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁵⁸ Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.
⁵⁹ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
⁶⁰ Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
⁶¹ Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA.
⁶² National Institute for Health and Welfare, Helsinki, Finland.
⁶³ Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁶⁴ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁶⁵ Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University, New York, New York, USA.
⁶⁶ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
⁶⁷ Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁶⁸ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁶⁹ NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
⁷⁰ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷¹ Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 28869590
PMCID: PMC5844224
DOI: 10.1038/ng.3943

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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Figures

**Figure 1**
A circular Manhattan plot summarizing the association results for the T2D scan. Black: Previously established T2D loci, Red: Previously unreported T2D loci from trans-ethnic meta-analysis, Blue: Previously unreported T2D loci from EUR only meta-analysis.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

References Online-Methods

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Research Materials