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Nat Genet. 2014 Apr;46(4):357-63. doi: 10.1038/ng.2915. Epub 2014 Mar 2.

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

Author information

1
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
2
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
3
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
4
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
5
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
6
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
7
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
8
1] Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
9
Department of Endocrinology and Metabolism, Landspitali University Hospital, Reykjavik, Iceland.
10
Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA.
11
1] Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. [2] Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. [3] Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. [4] Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
12
1] Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark. [2] Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
13
Cardiovascular & Metabolic Diseases Research Unit, Pfizer, Inc., Cambridge, Massachusetts, USA.
14
Cardiovascular and Metabolic Diseases Practice, Prescient Life Sciences, London, UK.
15
1] Department of Epidemiology and Biostatistics, Imperial College London, London, UK. [2] Imperial College Healthcare National Health Service (NHS) Trust, London, UK. [3] Ealing Hospital NHS Trust, Middlesex, UK.
16
Department of Biomedical Science, Hallym University, Chuncheon, Korea.
17
Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.
18
Unit of Diabetes and Celiac Diseases, Department of Clinical Sciences, Lund University, Malmö, Sweden.
19
1] Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. [2] Diabetes Care Unit, Vaasa Health Care Centre, Vaasa, Finland.
20
1] Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. [2] Israel Diabetes Research Group (IDRG), Holon, Israel.
21
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
22
1] Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [2] Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
23
Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Levanger, Norway.
24
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
25
1] Folkhalsan Research Centre, Helsinki, Finland. [2] Department of Social Services and Health Care, Jakobstad, Finland.
26
1] KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. [3] Department of Biomedicine, University of Bergen, Bergen, Norway.
27
1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. [2] Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [3] Faculty of Medicine, University of Aalborg, Aalborg, Denmark.
28
Steno Diabetes Center, Gentofte, Denmark.
29
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
30
1] Imperial College Healthcare National Health Service (NHS) Trust, London, UK. [2] Ealing Hospital NHS Trust, Middlesex, UK. [3] National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London, UK.
31
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
32
Department of Medicine, University of Eastern Finland, Kuopio Campus and Kuopio University Hospital, Kuopio, Finland.
33
Center for Genome Science, Korea National Institute of Health, Osong Health Technology, Chungcheongbuk-do, Korea.
34
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
35
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
36
1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. [2] Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [3] Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark.
37
Institute of Human Genetics, Technical University Munich, Munich, Germany.
38
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
39
1] KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway. [3] Department of Pathology, Haukeland University Hospital, Bergen, Norway.
40
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Department of Biostatistics, University of Liverpool, Liverpool, UK.
41
Applied Quantitative Genotherapeutics, Pfizer, Inc., South San Francisco, California, USA.
42
1] Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. [2] Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
43
National Institute for Health and Welfare (THL), Helsinki, Finland.
44
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
45
1] Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore. [2] Department of Medicine, National University of Singapore, National University Health System, Singapore. [3] Duke-National University of Singapore Graduate Medical School, Singapore.
46
1] Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore. [2] Centre for Molecular Epidemiology, National University of Singapore, Singapore. [3] Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore. [4] Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore. [5] Department of Statistics and Applied Probability, National University of Singapore, Singapore.
47
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
48
1] Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. [2] Folkhalsan Research Centre, Helsinki, Finland.
49
1] Centre for Vascular Prevention, Danube-University Krems, Krems, Austria. [2] Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. [3] Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
50
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. [3] Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
51
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
52
1] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [3] Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.
53
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. [3] Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
54
1] Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden. [2] Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland.
55
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [5] Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. [6] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [7] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

Abstract

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, 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) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. 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 risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. 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.

PMID:
24584071
PMCID:
PMC4051628
DOI:
10.1038/ng.2915
[Indexed for MEDLINE]
Free PMC Article
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