. 2020 Dec;13(6):e002769.

doi: 10.1161/CIRCGEN.119.002769. Epub 2020 Aug 13.

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus

Natalie R van Zuydam^{1

2

3}, Claes Ladenvall⁴, Benjamin F Voight^{5

6

7}, Rona J Strawbridge⁸, Juan Fernandez-Tajes³, N William Rayner^{2

3

9}, Neil R Robertson^{2

3}, Anubha Mahajan^{2

3}, Efthymia Vlachopoulou¹⁰, Anuj Goel^{3

11}, Marcus E Kleber, Christopher P Nelson^{12

13}, Lydia Coulter Kwee¹⁴, Tõnu Esko¹⁵, Evelin Mihailov¹⁵, Reedik Mägi¹⁵, Lili Milani¹⁵, Krista Fischer¹⁵, Stavroula Kanoni^{16

17

18

19

20}, Jitender Kumar^{21

22}, Ci Song^{21

23

24

25}, Jaana A Hartiala²⁶, Nancy L Pedersen²⁷, Markus Perola^{28

15

29}, Christian Gieger^{30

31

32}, Annette Peters^{30

32

33}, Liming Qu^{34

35

36}, Sara M Willems³⁷, Alex S F Doney³⁸, Andrew D Morris^{39

40}, Yan Zheng^{35

41}, Giorgio Sesti⁴², Frank B Hu^{35

43

44}, Lu Qi^{34

35

36}, Markku Laakso^{45

46}, Unnur Thorsteinsdottir⁴⁷, Harald Grallert^{30

31

48

49}, Cornelia van Duijn³⁷, Muredach P Reilly³⁴, Erik Ingelsson^{21

50

51

52}, Panos Deloukas^{17

53}, Sek Kathiresan^{16

17

18

19

20}, Andres Metspalu^{15

54}, Svati H Shah^{55

14}, Juha Sinisalo⁵⁶, Veikko Salomaa²⁹, Anders Hamsten⁸, Nilesh J Samani^{12

13}, Winfried März^{57

58}, Stanley L Hazen⁵⁹, Hugh Watkins^{3

11}, Danish Saleheen^{60

61}, Andrew P Morris^{3

62

63}, Helen M Colhoun^{64

65}, Leif Groop⁴, Mark I McCarthy^{2

3

66}, Colin N A Palmer¹; SUMMIT Steering Committee; CARDIOGRAMplusC4D Steering Committee*

Collaborators, Affiliations

Collaborators

SUMMIT Steering Committee; CARDIOGRAMplusC4D Steering Committee*:
John Danesh, Jeanette Erdmann, Dongfeng Gu, Jaspal S Kooner, Robert Roberts, Heribert Schunkert, Themistocles L Assimes, Stefan Blankenberg, Bernhard O Boehm, John C Chambers, Robert Clarke, Rory Collins, George Dedoussis, Paul W Franks, G Kees Hovingh, Bong-Jo Kim, Terho Lehtimäki, Ruth McPherson, Markku S Nieminen, Christopher O'Donnell, Samuli Ripatti, Manjinder S Sandhu, Stefan Schreiber, Agneta Siegbahn, Cristen J Willer, Pierre A Zalloua, Michael Mark, Timo Kanninen, Barbara Thorand, Giuseppe Remuzzi, David Dunger, Angela Shore, Ulf Smith, Per-Henrik Groop, Seppo Ylä-Herttuala, Claudio Cobelli, Riccardo Bellazzi, Ele Ferrannini, Carlo Patrono, Pirjo Nuutila, Paul McKeague, Birgit Steckel-Hamann, Li-Ming Gan, Everson Nogoceke, Piero Tortoli, Bernd Jablonka, Mary-Julia Brosnan

Affiliations

¹ Pat Macpherson Center for Pharmacogenetics & Pharmacogenomics, Cardiovascular & Diabetes Medicine (N.R.v.Z., C.N.A.P.), School of Medicine, University of Dundee.
² Oxford Center for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine (N.R.v.Z., N.W.R., N.R.R., A. Mahajan, M.I.Mc), University of Oxford, United Kingdom.
³ Wellcome Center for Human Genetics (N.R.v.Z., J.F.T., N.W.R., N.R.R, A. Mahajan, A.G., H.W., A.P.M., M.I.Mc), University of Oxford, United Kingdom.
⁴ Department of Clinical Sciences, Diabetes & Endocrinology, Lund University Diabetes Center, Malmö, Sweden (C.L., L.G.).
⁵ Department of Systems Pharmacology & Translational Therapeutics (B.F.V.).
⁶ Department of Genetics (B.F.V.).
⁷ Institute for Translational Medicine & Therapeutics (B.F.V.).
⁸ Cardiovascular Medicine Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden (R.J.S., A.H.).
⁹ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom (N.W.R.).
¹⁰ Transplantation Laboratory, Haartman Institute (E.V.), University of Helsinki, Helsinki, Finland.
¹¹ Division of Cardiovascular Medicine (A.G., H.W.), University of Oxford, United Kingdom.
¹² Department of Cardiovascular Sciences, University of Leicester (C.P.N., N.J.S.).
¹³ NIHR Leicester Biomedical Research Center, Glenfield Hospital, Leicester, United Kingdom (C.P.N., N.J.S.).
¹⁴ Duke Molecular Physiology Institute, Duke University, Durham, NC (L.C.K., S.H.S.).
¹⁵ Estonian Genome Center (T.E., E.M., R.M., L.M., K.F., M.P., A. Metspalu), University of Tartu, Tartu, Estonia.
¹⁶ Center for Genomic Health (S.K.), Queen Mary University of London, London, United Kingdom.
¹⁷ William Harvey Research Institute, Barts & the London Medical School (S.K., P.D.), Queen Mary University of London, London, United Kingdom.
¹⁸ Broad Institute of MIT & Harvard, Cambridge (S.K.).
¹⁹ Cardiology Division, Center for Human Genetic Research (S.K.), Massachusetts General Hospital & Harvard Medical School, Boston, MA.
²⁰ Cardiovascular Research Center (S.K.), Massachusetts General Hospital & Harvard Medical School, Boston, MA.
²¹ Department of Medical Sciences, Molecular Epidemiology & Science for Life Laboratory (J.K., C.S., E.I.).
²² Center for Computational Biology & Bioinformatics, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India (J.K.).
²³ Department of Immunology, Genetics and Pathology, Medical Genetics & Genomics, Uppsala University, Uppsala, Sweden (C.S.).
²⁴ Framingham Heart Study (C.S.).
²⁵ Population Sciences Branch, National Heart, Lung & Blood Institute, National Institute of Health, Framingham, MA (C.S.).
²⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA (J.A.H.).
²⁷ Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden (N.L.P.).
²⁸ Research Program for Clinical & Molecular Metabolism, Faculty of Medicine (M.P.), University of Helsinki, Helsinki, Finland. Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
²⁹ National Institute for Health and Welfare, Helsinki, Finland (M.P., V.S.).
³⁰ German Center for Diabetes Research (DZD), München-Neuherberg (C.G., A.P., H.G.).
³¹ Clinical Cooperation Group Type 2 Diabetes (C.G., H.G.), Helmholtz Zentrum München, Neuherberg, Germany.
³² German Research Center for Environmental Health & Institute of Genetic Epidemiology (C.G., A.P.), Helmholtz Zentrum München, Neuherberg, Germany.
³³ DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (A.P.).
³⁴ Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (L.Q., M.P.R.).
³⁵ Department of Nutrition (Y.Z., F.B.H., L.Q.).
³⁶ Department of Epidemiology, School of Public Health & Tropical Medicine, Tulane University, New Orleans, LA (L.Q.).
³⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (S.M.W., C.v.D.).
³⁸ Division of Molecular & Clinical Medicine (A.S.F.D.), School of Medicine, University of Dundee.
³⁹ The Usher Institute of Population Health Sciences & Informatics (A.D.M.), University of Edinburgh, Edinburgh, U.K.
⁴⁰ Health Data Research UK, London, United Kingdom (A.D.M.).
⁴¹ Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China (Y.Z.).
⁴² University "Magna Graecia" of Catanzaro, Italy (G.S.).
⁴³ Department of Epidemiology, Harvard School of Public Health, Boston, MA (F.B.H.).
⁴⁴ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, MA (F.B.H.).
⁴⁵ Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland (M.L.).
⁴⁶ Kuopio University Hospital, Finland (M.L.).
⁴⁷ Faculty of Medicine, University of Iceland. deCODE Genetics, Reykjavik, Iceland (U.T.).
⁴⁸ Research Unit of Molecular Epidemiology, Institute of Epidemiology (H.G.), Helmholtz Zentrum München, Neuherberg, Germany.
⁴⁹ Clinical Cooperation Group Nutrigenomics & Type 2 Diabetes (H.G.), Helmholtz Zentrum München, Neuherberg, Germany.
⁵⁰ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine (E.I.).
⁵¹ Stanford Cardiovascular Institute (E.I.).
⁵² Stanford Diabetes Research Center, Stanford University, Stanford, CA (E.I.).
⁵³ Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia (P.D.).
⁵⁴ Institute of Cell & Molecular Biology (A. Metspalu), University of Tartu, Tartu, Estonia.
⁵⁵ Division of Cardiology, Department of Medicine, Duke University Medical Center (S.H.S.).
⁵⁶ Heart & Lung Center, Helsinki University Hospital (J.S.) and Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland.
⁵⁷ Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany (W.M.).
⁵⁸ Clinical Institute of Medical & Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.).
⁵⁹ Lerner Research Institute, Heart & Vascular Institute, Cleveland Clinic, Cleveland, OH (S.L.H.).
⁶⁰ Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, PA (D.S.).
⁶¹ Center for Non-Communicable Diseases, Karachi, Pakistan (D.S.).
⁶² Department of Biostatistics, University of Liverpool, Liverpool, U.K. (A.P.M.).
⁶³ Division of Musculoskeletal & Dermatological Sciences, University of Manchester, Manchester, U.K. (A.P.M.).
⁶⁴ MRC Institute of Genetics & Molecular Medicine (H.M.C.), University of Edinburgh, Edinburgh, U.K.
⁶⁵ Public Health, NHS Fife, Kirkcaldy, Fife, U.K. (H.M.C.).
⁶⁶ Oxford NIHR Biomedical Research Center, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom (M.I.Mc).

PMID: 33321069
PMCID: PMC7748049
DOI: 10.1161/CIRCGEN.119.002769

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus

Natalie R van Zuydam et al. Circ Genom Precis Med. 2020 Dec.

. 2020 Dec;13(6):e002769.

doi: 10.1161/CIRCGEN.119.002769. Epub 2020 Aug 13.

Authors

Collaborators

SUMMIT Steering Committee; CARDIOGRAMplusC4D Steering Committee*:
John Danesh, Jeanette Erdmann, Dongfeng Gu, Jaspal S Kooner, Robert Roberts, Heribert Schunkert, Themistocles L Assimes, Stefan Blankenberg, Bernhard O Boehm, John C Chambers, Robert Clarke, Rory Collins, George Dedoussis, Paul W Franks, G Kees Hovingh, Bong-Jo Kim, Terho Lehtimäki, Ruth McPherson, Markku S Nieminen, Christopher O'Donnell, Samuli Ripatti, Manjinder S Sandhu, Stefan Schreiber, Agneta Siegbahn, Cristen J Willer, Pierre A Zalloua, Michael Mark, Timo Kanninen, Barbara Thorand, Giuseppe Remuzzi, David Dunger, Angela Shore, Ulf Smith, Per-Henrik Groop, Seppo Ylä-Herttuala, Claudio Cobelli, Riccardo Bellazzi, Ele Ferrannini, Carlo Patrono, Pirjo Nuutila, Paul McKeague, Birgit Steckel-Hamann, Li-Ming Gan, Everson Nogoceke, Piero Tortoli, Bernd Jablonka, Mary-Julia Brosnan

Affiliations

¹ Pat Macpherson Center for Pharmacogenetics & Pharmacogenomics, Cardiovascular & Diabetes Medicine (N.R.v.Z., C.N.A.P.), School of Medicine, University of Dundee.
² Oxford Center for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine (N.R.v.Z., N.W.R., N.R.R., A. Mahajan, M.I.Mc), University of Oxford, United Kingdom.
³ Wellcome Center for Human Genetics (N.R.v.Z., J.F.T., N.W.R., N.R.R, A. Mahajan, A.G., H.W., A.P.M., M.I.Mc), University of Oxford, United Kingdom.
⁴ Department of Clinical Sciences, Diabetes & Endocrinology, Lund University Diabetes Center, Malmö, Sweden (C.L., L.G.).
⁵ Department of Systems Pharmacology & Translational Therapeutics (B.F.V.).
⁶ Department of Genetics (B.F.V.).
⁷ Institute for Translational Medicine & Therapeutics (B.F.V.).
⁸ Cardiovascular Medicine Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden (R.J.S., A.H.).
⁹ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom (N.W.R.).
¹⁰ Transplantation Laboratory, Haartman Institute (E.V.), University of Helsinki, Helsinki, Finland.
¹¹ Division of Cardiovascular Medicine (A.G., H.W.), University of Oxford, United Kingdom.
¹² Department of Cardiovascular Sciences, University of Leicester (C.P.N., N.J.S.).
¹³ NIHR Leicester Biomedical Research Center, Glenfield Hospital, Leicester, United Kingdom (C.P.N., N.J.S.).
¹⁴ Duke Molecular Physiology Institute, Duke University, Durham, NC (L.C.K., S.H.S.).
¹⁵ Estonian Genome Center (T.E., E.M., R.M., L.M., K.F., M.P., A. Metspalu), University of Tartu, Tartu, Estonia.
¹⁶ Center for Genomic Health (S.K.), Queen Mary University of London, London, United Kingdom.
¹⁷ William Harvey Research Institute, Barts & the London Medical School (S.K., P.D.), Queen Mary University of London, London, United Kingdom.
¹⁸ Broad Institute of MIT & Harvard, Cambridge (S.K.).
¹⁹ Cardiology Division, Center for Human Genetic Research (S.K.), Massachusetts General Hospital & Harvard Medical School, Boston, MA.
²⁰ Cardiovascular Research Center (S.K.), Massachusetts General Hospital & Harvard Medical School, Boston, MA.
²¹ Department of Medical Sciences, Molecular Epidemiology & Science for Life Laboratory (J.K., C.S., E.I.).
²² Center for Computational Biology & Bioinformatics, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India (J.K.).
²³ Department of Immunology, Genetics and Pathology, Medical Genetics & Genomics, Uppsala University, Uppsala, Sweden (C.S.).
²⁴ Framingham Heart Study (C.S.).
²⁵ Population Sciences Branch, National Heart, Lung & Blood Institute, National Institute of Health, Framingham, MA (C.S.).
²⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA (J.A.H.).
²⁷ Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden (N.L.P.).
²⁸ Research Program for Clinical & Molecular Metabolism, Faculty of Medicine (M.P.), University of Helsinki, Helsinki, Finland. Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
²⁹ National Institute for Health and Welfare, Helsinki, Finland (M.P., V.S.).
³⁰ German Center for Diabetes Research (DZD), München-Neuherberg (C.G., A.P., H.G.).
³¹ Clinical Cooperation Group Type 2 Diabetes (C.G., H.G.), Helmholtz Zentrum München, Neuherberg, Germany.
³² German Research Center for Environmental Health & Institute of Genetic Epidemiology (C.G., A.P.), Helmholtz Zentrum München, Neuherberg, Germany.
³³ DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (A.P.).
³⁴ Cardiovascular Institute, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (L.Q., M.P.R.).
³⁵ Department of Nutrition (Y.Z., F.B.H., L.Q.).
³⁶ Department of Epidemiology, School of Public Health & Tropical Medicine, Tulane University, New Orleans, LA (L.Q.).
³⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands (S.M.W., C.v.D.).
³⁸ Division of Molecular & Clinical Medicine (A.S.F.D.), School of Medicine, University of Dundee.
³⁹ The Usher Institute of Population Health Sciences & Informatics (A.D.M.), University of Edinburgh, Edinburgh, U.K.
⁴⁰ Health Data Research UK, London, United Kingdom (A.D.M.).
⁴¹ Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China (Y.Z.).
⁴² University "Magna Graecia" of Catanzaro, Italy (G.S.).
⁴³ Department of Epidemiology, Harvard School of Public Health, Boston, MA (F.B.H.).
⁴⁴ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, MA (F.B.H.).
⁴⁵ Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland (M.L.).
⁴⁶ Kuopio University Hospital, Finland (M.L.).
⁴⁷ Faculty of Medicine, University of Iceland. deCODE Genetics, Reykjavik, Iceland (U.T.).
⁴⁸ Research Unit of Molecular Epidemiology, Institute of Epidemiology (H.G.), Helmholtz Zentrum München, Neuherberg, Germany.
⁴⁹ Clinical Cooperation Group Nutrigenomics & Type 2 Diabetes (H.G.), Helmholtz Zentrum München, Neuherberg, Germany.
⁵⁰ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine (E.I.).
⁵¹ Stanford Cardiovascular Institute (E.I.).
⁵² Stanford Diabetes Research Center, Stanford University, Stanford, CA (E.I.).
⁵³ Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia (P.D.).
⁵⁴ Institute of Cell & Molecular Biology (A. Metspalu), University of Tartu, Tartu, Estonia.
⁵⁵ Division of Cardiology, Department of Medicine, Duke University Medical Center (S.H.S.).
⁵⁶ Heart & Lung Center, Helsinki University Hospital (J.S.) and Institute for Molecular Medicine Finland (FIMM), Helsinki University, Helsinki, Finland.
⁵⁷ Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany (W.M.).
⁵⁸ Clinical Institute of Medical & Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.).
⁵⁹ Lerner Research Institute, Heart & Vascular Institute, Cleveland Clinic, Cleveland, OH (S.L.H.).
⁶⁰ Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, PA (D.S.).
⁶¹ Center for Non-Communicable Diseases, Karachi, Pakistan (D.S.).
⁶² Department of Biostatistics, University of Liverpool, Liverpool, U.K. (A.P.M.).
⁶³ Division of Musculoskeletal & Dermatological Sciences, University of Manchester, Manchester, U.K. (A.P.M.).
⁶⁴ MRC Institute of Genetics & Molecular Medicine (H.M.C.), University of Edinburgh, Edinburgh, U.K.
⁶⁵ Public Health, NHS Fife, Kirkcaldy, Fife, U.K. (H.M.C.).
⁶⁶ Oxford NIHR Biomedical Research Center, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom (M.I.Mc).

PMID: 33321069
PMCID: PMC7748049
DOI: 10.1161/CIRCGEN.119.002769

Abstract

Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D).

Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D).

Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background.

Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.

Keywords: blood pressure; coronary artery disease; diabetes mellitus; genome-wide association study; risk factors.

PubMed Disclaimer

Conflict of interest statement

Authors have disclosed possible conflicts of interest and have confirmed that these are unrelated to the work described in this article. Dr Ingelsson is a scientific advisor for Precision Wellness. Dr Salomaa has consulted for Novo Nordisk and Sanofi and has ongoing research collaboration with Bayer (all unrelated to the present study). Dr März reports employment with Synlab Holding Deutschland GmbH and has received grants or personal fees from Abbott Diagnostics; Aegerion Pharmaceuticals; AMGEN; AstraZeneca; BASF Pharma Solutions; Danone Research; MSD; Sanofi; Siemens Diagnostics; and Synageva. Dr Colhoun receives research support and honoraria from and is also a member of the advisory panels and speaker’s bureaus for Sanofi Aventis, Regeneron, and Eli Lilly. Dr Colhoun has been a member of Data and Safety Monitoring Board of the Advisory Panel for the CANTOS Trial (Canakinumab. Anti-Inflammatory Thrombosis Outcome Study; Novartis Pharmaceuticals). Dr Colhoun also receives or has recently received nonbinding research support from Roche Pharmaceuticals, Pfizer, Inc, Boehringer Ingelheim, and AstraZeneca. Dr Colhoun is a shareholder of Roche Pharmaceuticals and Bayer. Dr McCarthy has served on advisory panels for Pfizer, NovoNordisk, and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly, and research funding from Abbvie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, Dr McCarthy is an employee of Genentech and a holder of Roche stock. As of September 2019, Dr van Zuydam is an employee of AstraZeneca. As of 2016, Dr Vlachopoulou is an employee of Medpace. The other authors report no conflicts.

Figures

**Figure 1.**
**Study design.** In the discovery meta-analyses, we performed 4 different meta-analyses of coronary artery disease (CAD): in all individuals irrespective of Type 2 diabetes mellitus (T2D) status; in all individuals corrected for T2D stats; and stratified by T2D status. We examined allelic effects within strata to identify stratum-specific CAD associated variants, and between strata to identify variants that may interact with T2D status to modify the risk of CAD. We selected variants that achieved P<1×10^-4 for association with CAD in at least one of the following analyses: all individuals combined regardless of T2D status; subjects with T2D only; subjects without diabetes mellitus; or the interaction analysis. The replication analysis was performed in independent samples using the same study design as the discovery analysis. CARDIoGRAMplusC4D indicates Coronary Artery Disease Genome Wide Replication and Meta-Analysis (CARDIoGRAM) Plus the Coronary Artery Disease (C4D) Genetics; ENGAGE, European Network for Genetic and Genomic Epidemiology; HPFS, Health Professionals Follow-Up Study; METSIM, The Metabolic Syndrome in Men Study; NHS, Nurses’ Health Study; and SUMMIT, Surrogate Markers for Micro- and Macro-Vascular Hard End Points for Innovative Diabetes Tools.

**Figure 2.**
**Five genetic association study meta-analyses were performed to investigate the genetic architecture of coronary artery disease (CAD) in the context of Type 2 diabetes mellitus (T2D).** Manhattan and QQ plots from (A) a meta-analysis that combined allelic effects on CAD from subjects with T2D status and without diabetes mellitus and (B) corrected for T2D status to identify variants associated with CAD irrespective of T2D status; (C) a meta-analysis of allelic effects on CAD in subjects with T2D to identify loci that may influence the development of CAD in the context of T2D; (D) a meta-analysis of allelic effects on CAD in the absence of diabetes mellitus to identify loci that may influence the development of CAD in the absence of diabetes mellitus; and (E) an interaction analysis to identify loci that may interact with T2D to modify the risk of CAD. The effective sample size was based on the combined discovery and replication sample of 184 250 subjects.

See this image and copyright information in PMC

References

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Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus

Collaborators

Affiliations

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

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