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

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 Sapkota; Nabi 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; null 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; Børge G Nordestgaard; Anne Tybjaerg-Hansen; Marianne Benn; Ruth Frikke-Schmidt; CHD Exome+ Consortium

doi:10.1038/ng.3943

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

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 Sapkota, Nabi Shah, Sehrish Jabeen, Praveen SurendranYingchang 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, Børge G Nordestgaard, Anne Tybjaerg-Hansen, Marianne Benn, Ruth Frikke-Schmidt, CHD Exome+ Consortium

Department of Clinical Medicine

91 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 language	English
Journal	Nature Genetics
Volume	49
Issue number	10
Pages (from-to)	1450-1457
Number of pages	8
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3943
Publication status	Published - 1 Oct 2017

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., Sapkota, B. R., Shah, N., Jabeen, S., ... CHD Exome+ Consortium (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

Zhao, W, Rasheed, A, Tikkanen, E, Lee, J-J, Butterworth, AS, Howson, JMM, Assimes, TL, Chowdhury, R, Orho-Melander, M, Damrauer, S, Small, A, Asma, S, Imamura, M, Yamauch, T, Chambers, JC, Chen, P, Sapkota, BR, Shah, N, Jabeen, S, Surendran, P, Lu, Y, Zhang, W, Imran, A, Abbas, S, Majeed, F, Trindade, K, Qamar, N, Mallick, NH, Yaqoob, Z, Saghir, T, Rizvi, SNH, Memon, A, Rasheed, SZ, Memon, F-U-R, Mehmood, K, Ahmed, N, Qureshi, IH, Tanveer-Us-Salam, Iqbal, W, Malik, U, Mehra, N, Kuo, JZ, Sheu, WH-H, Guo, X, Hsiung, CA, Juang, J-MJ, Nordestgaard, BG , Tybjaerg-Hansen, A , Benn, M , Frikke-Schmidt, R & CHD Exome+ Consortium 2017, 'Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease', Nature Genetics, vol. 49, no. 10, pp. 1450-1457. https://doi.org/10.1038/ng.3943

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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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AU - Zhao, Wei

AU - Rasheed, Asif

AU - Tikkanen, Emmi

AU - Lee, Jung-Jin

AU - Butterworth, Adam S

AU - Howson, Joanna M M

AU - Assimes, Themistocles L

AU - Chowdhury, Rajiv

AU - Orho-Melander, Marju

AU - Damrauer, Scott

AU - Small, Aeron

AU - Asma, Senay

AU - Imamura, Minako

AU - Yamauch, Toshimasa

AU - Chambers, John C

AU - Chen, Peng

AU - Sapkota, Bishwa R

AU - Shah, Nabi

AU - Jabeen, Sehrish

AU - Surendran, Praveen

AU - Lu, Yingchang

AU - Zhang, Weihua

AU - Imran, Atif

AU - Abbas, Shahid

AU - Majeed, Faisal

AU - Trindade, Kevin

AU - Qamar, Nadeem

AU - Mallick, Nadeem Hayyat

AU - Yaqoob, Zia

AU - Saghir, Tahir

AU - Rizvi, Syed Nadeem Hasan

AU - Memon, Anis

AU - Rasheed, Syed Zahed

AU - Memon, Fazal-Ur-Rehman

AU - Mehmood, Khalid

AU - Ahmed, Naveeduddin

AU - Qureshi, Irshad Hussain

AU - Tanveer-Us-Salam, null

AU - Iqbal, Wasim

AU - Malik, Uzma

AU - Mehra, Narinder

AU - Kuo, Jane Z

AU - Sheu, Wayne H-H

AU - Guo, Xiuqing

AU - Hsiung, Chao A

AU - Juang, Jyh-Ming J

AU - Nordestgaard, Børge G

AU - Tybjaerg-Hansen, Anne

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N2 - 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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KW - Biomarkers

KW - Comorbidity

KW - Coronary Disease

KW - Diabetes Mellitus, Type 2

KW - Europe

KW - European Continental Ancestry Group

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - HLA-DRB5 Chains

KW - Humans

KW - Metabolic Networks and Pathways

KW - Metabolic Syndrome X

KW - Molecular Targeted Therapy

KW - Mutation, Missense

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Comparative Study

KW - Journal Article

U2 - 10.1038/ng.3943

DO - 10.1038/ng.3943

M3 - Journal article

C2 - 28869590

SN - 1061-4036

VL - 49

SP - 1450

EP - 1457

JO - Nature: New biology

JF - Nature: New biology

IS - 10

ER -

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

Abstract

Keywords

UN SDGs

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