Letter | Published:

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Nature Genetics volume 46, pages 357363 (2014) | Download Citation

Abstract

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of 150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)4 and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels5,6,7. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10−4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk8,9, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts10,11,12,13,14,15. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

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Acknowledgements

This manuscript is dedicated to the memory of David R. Cox, our dear friend and colleague, who was relentlessly supportive of this work—and more generally, of the use of human genetics to improve human health. He is missed, but his legacy goes on. We gratefully acknowledge the contribution of all 150,000 participants from the various population studies that contributed to this work. J.F. was supported in part by US National Institutes of Health (NIH) Training Grant 5-T32-GM007748-33. D.A. was supported by funding from the Doris Duke Charitable Foundation (2006087). N.L.B. was supported by a Fulbright Diabetes UK Fellowship (BDA 11/0004348). This work was supported in part by funding to the Broad Institute (principal investigator D.A.) from Pfizer, Inc. Funding for the GoT2D and T2D-GENES studies was provided by grants 5U01DK085526 (NIH/NIDDK; Multiethnic Study of Type 2 Diabetes Genes), DK088389 (NIH/NIDDK; Low-Pass Sequencing and High-Density SNP Genotyping for Type 2 Diabetes) and U54HG003067 (National Human Genome Research Institute (NHGRI); Large-Scale Sequencing and Analysis of Genomes), as well as by NIH grants U01 DK085501, U01 DK085524, U01 DK085545 and U01 DK085584. The Malmö Preventive Project and the Scania Diabetes Registry were supported by grants from the Swedish Research Council (Dnr 521-2010-3490 to L.G. and Dnr 349-2006-237 to the Lund University Diabetes Centre), as well as by a European Research Council (ERC) grant (GENETARGET T2D, GA269045) and two European Union grants (ENGAGE (2007-201413) and CEED3 (2008-223211)) to L.G. The Botnia study was supported by funding from the Sigrid Juselius Foundation and the Folkhälsan Research Foundation. P.R.N. was funded by the ERC (AdG 293574), the Research Council of Norway (197064/V50), the KG Jebsen Foundation, the University of Bergen, the Western Norway Health Authority, the European Association for the Study of Diabetes Sabbatical Leave Programme and Innovest. The Danish studies were supported by the Lundbeck Foundation (Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp); http://www.lucamp.org/) and the Danish Council for Independent Research. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/). The PIVUS/ULSAM cohort was supported by Wellcome Trust grants WT098017, WT064890 and WT090532, Uppsala University, the Uppsala University Hospital, the Swedish Research Council and the Swedish Heart-Lung Foundation. The METSIM study was supported by the Academy of Finland (contract 124243), the Finnish Heart Foundation, the Finnish Diabetes Foundation, Tekes (contract 1510/31/06), the Commission of the European Community (HEALTH-F2-2007-201681) and grants R01DK062370 and R01DK072193 (NIH/NIDDK) and grant Z01HG000024 (NHGRI). The FUSION study was supported by grants R01DK062370 and R01DK072193 (NIH/NIDDK) and grant Z01HG000024 (NHGRI). The DR's EXTRA Study was supported by the Ministry of Education and Culture of Finland (627; 2004-2011), the Academy of Finland (102318; 123885), Kuopio University Hospital, the Finnish Diabetes Association, the Finnish Heart Association and the Päivikki and Sakari Sohlberg Foundation and by grants from the European Commission Framework Programme 6 Integrated Project (EXGENESIS); LSHM-CT-2004-005272, City of Kuopio and Social Insurance Institution of Finland (4/26/2010). V. Salomaa is funded by the Academy of Finland, grant 139635, and by the Finnish Foundation for Cardiovascular Disease. Sequencing and genotyping of British individuals was supported by Wellcome Trust grants WT090367, WT090532 and WT098381 and by NIH/NIDDK grant U01-DK085545. Funding for the Jackson Heart Study (JHS) was provided by the National Heart, Lung, and Blood Institute (NHLBI) and by the National Institute on Minority Health and Health Disparities (N01 HC-95170, N01 HC-95171 and N01 HC-95172). A.P.M. acknowledges support from Wellcome Trust grants WT098017, WT090532 and WT064890. F.V.-S. and H.S. were supported by the European Union Seventh Framework Programme, DIAPREPP (Diabetes Type 1 Prediction, Early Pathogenesis and Prevention, grant agreement 202013), and by the Swedish Child Diabetes Foundation (Barndiabetesfonden).

Author information

Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Jason Flannick
    • , Nicola L Beer
    • , Suzanne B R Jacobs
    • , Noël P Burtt
    • , Zachary Dymek
    • , Yossi Farjoun
    • , Timothy Fennell
    • , Pierre Fontanillas
    • , Stacey Gabriel
    • , Sekar Kathiresan
    • , Cecilia M Lindgren
    • , Ayellet V Segrè
    • , Benjamin F Voight
    • , Pål R Njølstad
    •  & David Altshuler
  2. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jason Flannick
    • , Ayellet V Segrè
    •  & David Altshuler
  3. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jason Flannick
    •  & David Altshuler
  4. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Daniel F Gudbjartsson
    • , Augustine Kong
    • , Gisli Masson
    • , Valgerdur Steinthorsdottir
    • , Patrick Sulem
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  5. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Nicola L Beer
    •  & Mark I McCarthy
  6. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Niels Grarup
    • , Torben Hansen
    • , Rasmus Ribel-Madsen
    •  & Oluf Pedersen
  7. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Anubha Mahajan
    • , Erik Ingelsson
    • , Cecilia M Lindgren
    • , Andrew P Morris
    •  & Mark I McCarthy
  8. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Christian Fuchsberger
    • , Heather M Stringham
    • , Tanya Teslovich
    •  & Michael Boehnke
  9. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Gil Atzmon
  10. Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Gil Atzmon
  11. Department of Endocrinology and Metabolism, Landspitali University Hospital, Reykjavik, Iceland.

    • Rafn Benediktsson
    •  & Astradur B Hreidarsson
  12. Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA.

    • John Blangero
    •  & Ravindranath Duggirala
  13. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Don W Bowden
  14. Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Don W Bowden
  15. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Don W Bowden
  16. Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Don W Bowden
  17. Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark.

    • Ivan Brandslund
  18. Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.

    • Ivan Brandslund
  19. Cardiovascular & Metabolic Diseases Research Unit, Pfizer, Inc., Cambridge, Massachusetts, USA.

    • Julia Brosnan
    • , Ann-Marie Richard
    • , Tim Rolph
    •  & Jeff K Trimmer
  20. Cardiovascular and Metabolic Diseases Practice, Prescient Life Sciences, London, UK.

    • Frank Burslem
  21. Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

    • John Chambers
  22. Imperial College Healthcare National Health Service (NHS) Trust, London, UK.

    • John Chambers
    •  & Jaspal Kooner
  23. Ealing Hospital NHS Trust, Middlesex, UK.

    • John Chambers
    •  & Jaspal Kooner
  24. Department of Biomedical Science, Hallym University, Chuncheon, Korea.

    • Yoon Shin Cho
  25. Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.

    • Cramer Christensen
  26. Unit of Diabetes and Celiac Diseases, Department of Clinical Sciences, Lund University, Malmö, Sweden.

    • Desirée A Douglas
    • , Hanna Skärstrand
    •  & Fariba Vaziri-Sani
  27. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Tom Forsén
    •  & Tiinamaija Tuomi
  28. Diabetes Care Unit, Vaasa Health Care Centre, Vaasa, Finland.

    • Tom Forsén
  29. Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

    • Benjamin Glaser
  30. Israel Diabetes Research Group (IDRG), Holon, Israel.

    • Benjamin Glaser
  31. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Craig Hanis
  32. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

    • Torben Hansen
  33. Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Levanger, Norway.

    • Kristian Hveem
  34. Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Erik Ingelsson
  35. Folkhalsan Research Centre, Helsinki, Finland.

    • Bo Isomaa
    •  & Tiinamaija Tuomi
  36. Department of Social Services and Health Care, Jakobstad, Finland.

    • Bo Isomaa
  37. KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Stefan Johansson
    • , Anders Molven
    •  & Pål R Njølstad
  38. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.

    • Stefan Johansson
  39. Department of Biomedicine, University of Bergen, Bergen, Norway.

    • Stefan Johansson
  40. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.

    • Torben Jørgensen
    •  & Allan Linneberg
  41. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Torben Jørgensen
    •  & Allan Linneberg
  42. Faculty of Medicine, University of Aalborg, Aalborg, Denmark.

    • Torben Jørgensen
  43. Steno Diabetes Center, Gentofte, Denmark.

    • Marit Eika Jørgensen
  44. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan
    •  & David Altshuler
  45. Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan
    •  & David Altshuler
  46. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Sekar Kathiresan
  47. National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London, UK.

    • Jaspal Kooner
  48. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.

    • Jasmina Kravic
    •  & Leif Groop
  49. Department of Medicine, University of Eastern Finland, Kuopio Campus and Kuopio University Hospital, Kuopio, Finland.

    • Markku Laakso
  50. Center for Genome Science, Korea National Institute of Health, Osong Health Technology, Chungcheongbuk-do, Korea.

    • Jong-Young Lee
  51. Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Lars Lind
  52. Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark.

    • Allan Linneberg
  53. Institute of Human Genetics, Technical University Munich, Munich, Germany.

    • Thomas Meitinger
  54. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Karen L Mohlke
  55. Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

    • Anders Molven
  56. Department of Pathology, Haukeland University Hospital, Bergen, Norway.

    • Anders Molven
  57. Department of Biostatistics, University of Liverpool, Liverpool, UK.

    • Andrew P Morris
  58. Applied Quantitative Genotherapeutics, Pfizer, Inc., South San Francisco, California, USA.

    • Shobha Potluri
    •  & David R Cox
  59. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.

    • Rainer Rauramaa
  60. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.

    • Rainer Rauramaa
  61. National Institute for Health and Welfare (THL), Helsinki, Finland.

    • Veikko Salomaa
  62. Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore.

    • E Shyong Tai
    •  & Yik Ying Teo
  63. Department of Medicine, National University of Singapore, National University Health System, Singapore.

    • E Shyong Tai
  64. Duke–National University of Singapore Graduate Medical School, Singapore.

    • E Shyong Tai
  65. Centre for Molecular Epidemiology, National University of Singapore, Singapore.

    • Yik Ying Teo
  66. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.

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

    • Yik Ying Teo
  68. Department of Statistics and Applied Probability, National University of Singapore, Singapore.

    • Yik Ying Teo
  69. Faculty of Medicine, University of Iceland, Reykjavík, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson
  70. Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.

    • Jaakko Tuomilehto
  71. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Tuomilehto
  72. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Jaakko Tuomilehto
  73. Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

    • Benjamin F Voight
  74. Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

    • Benjamin F Voight
  75. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • James G Wilson
  76. Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  77. Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.

    • Pål R Njølstad
  78. Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland.

    • Leif Groop
  79. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  80. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • David Altshuler

Consortia

  1. Go-T2D Consortium

    Full lists of members and affiliations appear in the Supplementary Note.

  2. T2D-GENES Consortium

    Full lists of members and affiliations appear in the Supplementary Note.

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Contributions

This manuscript describes an analysis spanning four initially distinct sequencing studies—a collaborative project between Pfizer, Massachusetts General Hospital, the Broad Institute and Lund University entitled “Towards Therapeutic Targets for Type 2 Diabetes and Myocardial Infarction in the Background of Type 2 Diabetes” (PMBL), an effort by deCODE Genetics to use whole-genome sequencing and imputation to identify and genotype over 35 million variants in up to 370,000 Icelanders23, the Genetics of Type 2 Diabetes (GoT2D) project and the Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) project—as well as four additional genotyping efforts. The overall study bringing together data from these efforts was coordinated by J.F. and D.A., with final analysis combining data from all variants collected by J.F. The manuscript was written by J.F., D.A. and K.S., and all authors reviewed, edited and approved the manuscript. Author contributions specific to the sequencing or genotyping studies are as follows.

Pfizer, Massachusetts General Hospital, Broad Institute and Lund University. Study design. B.F.V., F.B., S.P., N.P.B., D.R.C., T.R., L.G., S.K. and D.A. Clinical investigation and sample management. T. Forsén, B.I., T. Tuomi, L.G. and J. Kravic. Sequencing, genotyping and data processing. N.P.B., T. Fennell and S.G.; performed at the Broad Institute. Analysis. J.F. (p.Arg138*) and A.V.S. (p.Trp325Arg). Functional studies. N.L.B., S.B.R.J., Z.D. (cellular models), F.V.-S., H.S. and D.A.D. (screen for carrier autoantibodies). Leadership and management. N.P.B., A.-M.R., J. Brosnan, J.K.T., S.K., T.R., L.G., D.R.C. and D.A.

deCODE Genetics. Clinical investigation and sample management. A.B.H. and R.B. Sequencing, genotyping and data processing. G.T., V. Steinthorsdottir, P.S., G.M., D.F.G. and A.K.; performed at deCODE Genetics. Analysis. G.T., V. Steinthorsdottir, P.S., G.M., D.F.G. and A.K. Leadership and management. A.K., U.T. and K.S.

T2D-GENES and Go-T2D.Clinical investigation and sample management. G.A., J. Blangero, D.W.B., J.C., Y.S.C., R.D., B.G., C.H., J. Kooner, M.L., T.M., J.-Y.L., E.S.T., Y.Y.T. and J.G.W. Sequencing and data processing. N.P.B., Y.F., T. Fennell and S.G.; performed at the Broad Institute. Analysis. J.F. (SLC30A8), P.F., A.P.M. and T. Teslovich (exome wide). Leadership and management. M.I.M., M.B. and D.A. HUNT2 sample management, genotyping, analysis and leadership involved K.H., A. Molven, S.J. and P.R.N. Danish sample management, genotyping, analysis and leadership involved N.G., R.R.-M., M.E.J., C.C., I.B., A.L., T.J., T.H. and O.P. PIVUS/ULSAM sample management, genotyping, analysis and leadership involved A. Mahajan, C.M.L., L.L., E.I. and A.P.M. Finnish sample management, genotyping, analysis and leadership involved C.F., H.M.S., M.L., K.L.M., R.R., V. Salomaa, J.T. and M.B.

Competing interests

G.T., V. Steinthorsdottir, P.S., G.M., D.F.G., A.K., U.T. and K.S. are employed by deCODE Genetics/Amgen, Inc. S.P., A.-M.R., J. Brosnan, J.K.T., T.R. and D.R.C. are employees of Pfizer, Inc. F.B. is a former employee of Pfizer, Inc., and retains shares in the company. All other authors declare no competing financial interests.

Corresponding authors

Correspondence to Kari Stefansson or David Altshuler.

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    Supplementary Data Set 1

    Sequence read data for variants called from additional sequencing.

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https://doi.org/10.1038/ng.2915

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