1 The Faculty of Medicine, Aalborg University, VBN2 Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, VBN3 unknown4 deCODE Genetics5 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 Genetics7 Center for Statistical Genetics, Department of Biostatistics, University of Michigan8 Department of Medicine, Albert Einstein College of Medicine9 Landspitali University Hospital10 Department of Genetics, Texas Biomedical Research Institute11 Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine12 Department of Clinical Biochemistry, Vejle Hospital13 Cardiovascular and Metabolic Diseases Research Unit, Pfizer, Inc.14 Cardiovascular and Metabolic Diseases Practice15 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.16 Department of Biomedical Science, Hallym University17 Department of Internal Medicine and Endocrinology, Vejle Hospital18 Unit of Diabetes and Celiac Diseases, Department of Clinical Sciences, Lund University19 Department of General Practice and Primary Health Care, University of Helsinki20 Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center21 Human Genetics Center, University of Texas Health Science Center at Houston22 Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology23 Folkhalsan24 KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen25 Department of Health Science and Technology, The Faculty of Medicine, Aalborg University, VBN26 Steno Diabetes Center27 Imperial College Healthcare National Health Service (NHS) Trust28 Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre29 Department of Medicine, University of Eastern Finland, Kuopio Campus and Kuopio University Hospital30 Center for Genome Science, Korea National Institute of Health, Osong Health Technology31 Department of Medical Sciences, Uppsala University32 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.33 Institute of Human Genetics, Technical University Munich34 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.35 Applied Quantitative Genotherapeutics, Pfizer, Inc.36 Kuopio Research Institute of Exercise Medicine37 National Institute for Health and Welfare38 Saw Swee Hock School of Public Health, National University of Singapore, National University Health System39 Centre for Vascular Prevention, Danube-University Krems40 Department of Physiology and Biophysics, University of Mississippi Medical Center41 Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, UKWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UKOxford NIHR Biomedical Research Centre, Oxford, UK.42 deCODE Genetics43 Landspitali University Hospital44 Folkhalsan
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.
Nature Genetics, 2014, Vol 46, Issue 4, p. 357-363
Animals; Base Sequence; Blood Glucose; Cation Transport Proteins; Diabetes Mellitus, Type 2; Genetic Association Studies; Genotype; Humans; Ion Transport; Mice; Mice, Knockout; Molecular Sequence Data; Mutation, Missense; Proinsulin; Sequence Analysis, DNA