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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Nature Genetics, Volume 46, No. 4, Year 2014
Notification
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Description
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. © 2014 Nature America, Inc.
Authors & Co-Authors
Flannick, Jason A.
United States, Cambridge
Broad Institute
United States, Boston
Massachusetts General Hospital
Thorleifsson, Gudmar
Iceland, Reykjavik
Decode Genetics
Beer, Nicola L.
United States, Cambridge
Broad Institute
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Jacobs, Suzanne B.R.
United States, Cambridge
Broad Institute
Grarup, Niels
Denmark, Copenhagen
Novo Nordisk Foundation Center for Basic Metabolic Research
Burtt, Nöel P.
United States, Cambridge
Broad Institute
Mahajan, Anubha
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Fuchsberger, Christian
United States, Ann Arbor
University of Michigan, Ann Arbor
Atzmon, Gil
United States, New York
Albert Einstein College of Medicine of Yeshiva University
Benediktsson, Rafn
Iceland, Reykjavik
Landspitali - the National University Hospital of Iceland
Blangero, John C.
United States, San Antonio
Texas Biomedical Research Institute
Bowden, Donald W.
United States, Winston Salem
Wake Forest University School of Medicine
Brandslund, Ivan
Denmark, Vejle
Sygehus Lillebælt - Vejle
Denmark, Odense
Syddansk Universitet
Brosnan, Mary Julia
United States, New York
Pfizer Inc.
Burslem, Frank
United Kingdom, London
Cardiovascular and Metabolic Diseases Practice
Chambers, John Campbell
United Kingdom, London
Imperial College London
United Kingdom, London
Imperial College Healthcare Nhs Trust
United Kingdom, Harrow
London North West University Healthcare Nhs Trust
Cho, Yoon-shin
South Korea, Chuncheon
Hallym University
Christensen, Cramer Kjeldahl
Denmark, Vejle
Sygehus Lillebælt - Vejle
Douglas, Desirée A.
Sweden, Lund
Lunds Universitet
Duggirala, Ravindranath
United States, San Antonio
Texas Biomedical Research Institute
Dymek, Zachary
United States, Cambridge
Broad Institute
Farjoun, Yossi
United States, Cambridge
Broad Institute
Fennell, Timothy J.
United States, Cambridge
Broad Institute
Fontanillas, Pierre
United States, Cambridge
Broad Institute
Forsén, Tom J.
Finland, Helsinki
Helsingin Yliopisto
Finland, Vaasa
Vaasa Health Care Centre
Gabriel, Stacey Bolk
United States, Cambridge
Broad Institute
Glaser, Benjamin
Israel, Jerusalem
Hadassah University Medical Centre
Israel, Tel Aviv-yafo
Israel Diabetes Research Group Idrg
Gudbjartsson, Daníel Fannar
Iceland, Reykjavik
Decode Genetics
Hanis, Craig L.
United States, Houston
University of Texas Health Science Center at Houston
Hansen, Torben Frøstrup
Denmark, Copenhagen
Novo Nordisk Foundation Center for Basic Metabolic Research
Denmark, Odense
Faculty of Health Sciences, University of Southern Denmark
Hreidarsson, Ástrádur B.
Iceland, Reykjavik
Landspitali - the National University Hospital of Iceland
Hveem, Kristian
Norway, Trondheim
Norges Teknisk-naturvitenskapelige Universitet
Ingelsson, Erik
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Sweden, Solna
Science for Life Laboratory
Isomaa, Bo A.
Finland, Helsinki
Folkhälsan
Johansson, Stefan E.
Norway, Bergen
Universitetet I Bergen
Norway, Bergen
Haukeland Universitetssjukehus
Jörgensen, Torben J.
Denmark, Glostrup
Amtssygehuset I Glostrup
Denmark, Copenhagen
Det Sundhedsvidenskabelige Fakultet
Denmark, Aalborg
Aalborg University
Jørgensen, Marit E. Eika
Denmark, Herlev
Steno Diabetes Center Copenhagen
Kathiresan, Sekar
United States, Cambridge
Broad Institute
United States, Boston
Massachusetts General Hospital
United States, Boston
Harvard Medical School
Kong, Augustine
Iceland, Reykjavik
Decode Genetics
Kooner, Jaspal Singh
United Kingdom, London
Imperial College Healthcare Nhs Trust
United Kingdom, Harrow
London North West University Healthcare Nhs Trust
United Kingdom, London
National Heart and Lung Institute
Kravic, Jasmina
Sweden, Malmo
Lund University Diabetes Centre
Laakso, M. M.
Finland, Kuopio
Itä-suomen Yliopisto
Lee, Jongyoung
South Korea, Cheongju
Korea National Institute of Health
Lind, Lars L.
Sweden, Uppsala
Uppsala Universitet
Lindgren, Cecilia M.
United States, Cambridge
Broad Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Linneberg, Allan R.
Denmark, Glostrup
Amtssygehuset I Glostrup
Denmark, Copenhagen
Det Sundhedsvidenskabelige Fakultet
Másson, Gísli
Iceland, Reykjavik
Decode Genetics
Meitinger, Thomas A.
Germany, Munich
Technische Universität München
Mohlke, Karen
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Molven, Anders
Norway, Bergen
Universitetet I Bergen
Norway, Bergen
Haukeland Universitetssjukehus
Morris, Andrew Paul
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
United Kingdom, Liverpool
University of Liverpool
Potluri, Shobha
United States, New York
Pfizer Inc.
Rauramaa, Rainer
Finland, Kuopio
Itä-suomen Yliopisto
Finland, Kuopio
Kuopio University Hospital
Ribel-Madsen, Rasmus
Denmark, Copenhagen
Novo Nordisk Foundation Center for Basic Metabolic Research
Richard, Ann Marie T.
United States, New York
Pfizer Inc.
Rolph, Timothy P.
United States, New York
Pfizer Inc.
Salomaa, Veikko V.
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Segrè, Ayellet V.
United States, Cambridge
Broad Institute
United States, Boston
Massachusetts General Hospital
Skärstrand, Hanna
Sweden, Lund
Lunds Universitet
Steinthórsdóttir, Valgerdur
Iceland, Reykjavik
Decode Genetics
Stringham, Heather M.
United States, Ann Arbor
University of Michigan, Ann Arbor
Sulem, Patrick
Iceland, Reykjavik
Decode Genetics
Tai, E. Shyong
Singapore, Singapore City
National University Health System
Singapore, Singapore City
Duke-nus Medical School
Teo, Yik Ying
Singapore, Singapore City
National University Health System
Singapore, Singapore City
National University of Singapore
Singapore, Singapore City
A-star, Genome Institute of Singapore
Teslovich, Tanya M.
United States, Ann Arbor
University of Michigan, Ann Arbor
Thorsteinsdottir, Unnur Arna
Iceland, Reykjavik
Decode Genetics
Iceland, Reykjavik
Haskoli Islands
Trimmer, Jeff K.
United States, New York
Pfizer Inc.
Tuomi, Tiinamaija
Finland, Helsinki
Helsingin Yliopisto
Finland, Helsinki
Folkhälsan
Tuomilehto, Jaakko O.I.
Austria, Krems an Der Donau
Donau-universität Krems
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Saudi Arabia, Jeddah
King Abdulaziz University
Vaziri-Sani, Fariba
Sweden, Lund
Lunds Universitet
Voight, Benjamin F.
United States, Cambridge
Broad Institute
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Wilson, James Gaines
United States, University
University of Mississippi
Boehnke, Michael L.
United States, Ann Arbor
University of Michigan, Ann Arbor
McCarthy, Mark I.
United Kingdom, Oxford
University of Oxford Medical Sciences Division
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
United Kingdom, Oxford
Churchill Hospital
Njolstad, Pãl Rasmus
United States, Cambridge
Broad Institute
Norway, Bergen
Universitetet I Bergen
Norway, Bergen
Haukeland Universitetssjukehus
Pedersen, Oluf Borbye
Denmark, Copenhagen
Novo Nordisk Foundation Center for Basic Metabolic Research
Groop, Leif C.
Sweden, Malmo
Lund University Diabetes Centre
Finland, Helsinki
Helsingin Yliopisto
Cox, David R.
United States, New York
Pfizer Inc.
Stefánsson, Kári
Iceland, Reykjavik
Decode Genetics
Iceland, Reykjavik
Haskoli Islands
Altshuler, David M.
United States, Cambridge
Broad Institute
United States, Boston
Massachusetts General Hospital
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
Statistics
Citations: 80
Authors: 80
Affiliations: 57
Identifiers
Doi:
10.1038/ng.2915
ISSN:
10614036
e-ISSN:
15461718
Research Areas
Genetics And Genomics
Noncommunicable Diseases