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

Jason Flannick; Gudmar Thorleifsson; Nicola L. Beer; Suzanne B. R. Jacobs; Niels Grarup; Noel P. Burtt; Anubha Mahajan; Christian Fuchsberger; Gil Atzmon; Rafn Benediktsson; John Blangero; Don W. Bowden; Ivan Brandslund; Julia Brosnan; Frank Burslem; John Chambers; Yoon Shin Cho; Cramer Christensen; Desiree A. Douglas; Ravindranath Duggirala; Zachary Dymek; Yossi Farjoun; Timothy Fennell; Pierre Fontanillas; Tom Forsen; Stacey Gabriel; Benjamin Glaser; Daniel F. Gudbjartsson; Craig Hanis; Torben Hansen; Astradur B. Hreidarsson; Kristian Hveem; Erik Ingelsson; Bo Isomaa; Stefan Johansson; Torben Jorgensen; Marit Eika Jorgensen; Sekar Kathiresan; Augustine Kong; Jaspal Kooner; Jasmina Kravic; Markku Laakso; Jong-Young Lee; Lars Lind; Cecilia M. Lindgren; Allan Linneberg; Gisli Masson; Thomas Meitinger; Karen L. Mohlke; Anders Molven; Andrew P. Morris; Shobha Potluri; Rainer Rauramaa; Rasmus Ribel-Madsen; Ann-Marie Richard; Tim Rolph; Veikko Salomaa; Ayellet V. Segre; Hanna Skaerstrand; Valgerdur Steinthorsdottir; Heather M. Stringham; Patrick Sulem; E. Shyong Tai; Yik Ying Teo; Tanya Teslovich; Unnur Thorsteinsdottir; Jeff K. Trimmer; Tiinamaija Tuomi; Jaakko Tuomilehto; Fariba Vaziri-Sani; Benjamin F. Voight; James G. Wilson; Michael Boehnke; Mark I. McCarthy; Pal R. Njolstad; Oluf Pedersen; Leif Groop; David R. Cox; Kari Stefansson; David Altshuler; Go-T2D Consortium

doi:10.1038/ng.2915

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

Journal article

Peer reviewed

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

Jason Flannick, Gudmar Thorleifsson, Nicola L. Beer, Suzanne B. R. Jacobs, Niels Grarup, Noel P. Burtt, Anubha Mahajan, Christian Fuchsberger, Gil Atzmon, Rafn Benediktsson, …

Nature genetics, Vol.46(4), pp.357-363

01/04/2014

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

PMCID: PMC4051628

PMID: 24584071

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1-3, 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 levels5-7. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 x 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 x 10(-4)). The two most common proteintruncating 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(8,9), and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts(10-15). 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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Title: Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Creators - without role: Jason Flannick - Broad Institute
Gudmar Thorleifsson - deCODE Genetics
Nicola L. Beer - Oxford Centre for Diabetes, Endocrinology and Metabolism
Suzanne B. R. Jacobs - Broad Institute
Niels Grarup - Novo Nordisk Foundation
Noel P. Burtt - Broad Institute
Anubha Mahajan - Wellcome Centre for Human Genetics
Christian Fuchsberger - University of Michigan–Ann Arbor
Gil Atzmon - Albert Einstein College of Medicine
Rafn Benediktsson - Reykjavík University
John Blangero - Texas Biomedical Research Institute
Don W. Bowden - Wake Forest University
Ivan Brandslund - Vejle Sygehus
Julia Brosnan - Pfizer
Frank Burslem - Prescient Life Sci, Cardiovasc & Metab Dis Practice, London, England
John Chambers - National Health Service
Yoon Shin Cho - Hallym University
Cramer Christensen - Vejle Sygehus
Desiree A. Douglas - Lund University
Ravindranath Duggirala - Texas Biomedical Research Institute
Zachary Dymek - Broad Institute
Yossi Farjoun - Broad Institute
Timothy Fennell - Broad Institute
Pierre Fontanillas - Broad Institute
Tom Forsen - University of Helsinki
Stacey Gabriel - Broad Institute
Benjamin Glaser - Hadassah Medical Center
Daniel F. Gudbjartsson - deCODE Genetics
Craig Hanis - The University of Texas Health Science Center at Houston
Torben Hansen - Novo Nordisk Foundation
Astradur B. Hreidarsson - Reykjavík University
Kristian Hveem - Norwegian University of Science and Technology
Erik Ingelsson - Wellcome Centre for Human Genetics
Bo Isomaa - Folkhälsans Forskningscentrum
Stefan Johansson - Haukeland University Hospital
Torben Jorgensen - Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark
Marit Eika Jorgensen - Steno Diabet Ctr, DK-2820 Gentofte, Denmark
Sekar Kathiresan - Broad Institute
Augustine Kong - deCODE Genetics
Jaspal Kooner - Imperial College London
Jasmina Kravic - Lund University
Markku Laakso - Kuopio University Hospital
Jong-Young Lee - Korea National Institute of Health
Lars Lind - Uppsala University
Cecilia M. Lindgren - Broad Institute
Allan Linneberg - Glostrup Hospital
Gisli Masson - deCODE Genetics
Thomas Meitinger - Technical University of Munich
Karen L. Mohlke - University of North Carolina at Chapel Hill
Anders Molven - University of Bergen
Andrew P. Morris - University of Liverpool
Shobha Potluri - Pfizer
Rainer Rauramaa - Kuopio University Hospital
Rasmus Ribel-Madsen - Novo Nordisk Foundation
Ann-Marie Richard - Pfizer
Tim Rolph - Pfizer
Veikko Salomaa - Finnish Institute for Health and Welfare
Ayellet V. Segre - Broad Institute
Hanna Skaerstrand - Lund University
Valgerdur Steinthorsdottir - deCODE Genetics
Heather M. Stringham - University of Michigan–Ann Arbor
Patrick Sulem - deCODE Genetics
E. Shyong Tai - National University Health System
Yik Ying Teo - Duke-NUS Medical School
Tanya Teslovich - University of Michigan–Ann Arbor
Unnur Thorsteinsdottir - deCODE Genetics
Jeff K. Trimmer - Pfizer
Tiinamaija Tuomi - University of Helsinki
Jaakko Tuomilehto - King Abdulaziz University
Fariba Vaziri-Sani - Lund University
Benjamin F. Voight - Broad Institute
James G. Wilson - University of Mississippi Medical Center
Michael Boehnke - University of Michigan–Ann Arbor
Mark I. McCarthy - Oxford Centre for Diabetes, Endocrinology and Metabolism
Pal R. Njolstad - Broad Institute
Oluf Pedersen - Novo Nordisk Foundation
Leif Groop - Institute for Molecular Medicine Finland
David R. Cox - Pfizer
Kari Stefansson - deCODE Genetics
David Altshuler - Massachusetts General Hospital
Go-T2D Consortium
Publication Details: Nature genetics, Vol.46(4), pp.357-363
Publisher: Springer Nature
Number of pages: 8
Grant note: Dnr 521-2010-3490; Dnr 349-2006-237 / Swedish Research Council; Swedish Research Council for Health Working Life & Welfare (Forte); Swedish Research Council Formas N01 HC-95170; N01 HC-95171; N01 HC-95172 / National Institute on Minority Health and Health Disparities; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Minority Health & Health Disparities (NIMHD) BDA 11/0004348 / Fulbright Diabetes UK Fellowship; Diabetes UK 102318 / Academy of Finland (AKA); Research Council of Finland; Finnish Funding Agency for Technology & Innovation (TEKES) GENETARGET T2D; GA269045 / European Research Council (ERC); European Commission; Spanish Government 2008-223211 / CEED3 University of Bergen Novo Nordisk Foundation; Novocure Limited 1510/31/06 / Finnish Diabetes Foundation, Tekes HEALTH-F2-2007-201681 / Commission of the European Community; European Commission Finnish Foundation for Cardiovascular Disease European Union Seventh Framework Programme, DIAPREPP LSHM-CT-2004-005272 / European Commission Framework Programme 6 Integrated Project; Marie Curie Actions Uppsala University Folkh lsan Research Foundation 124243; 102318; 123885; 139635 / Academy of Finland; Research Council of Finland Finnish Heart Foundation Sigrid Juselius Foundation NF-SI-0611-10099 / National Institute for Health Research; National Institute for Health & Care Research (NIHR) 2006087 / Doris Duke Charitable Foundation; Doris Duke Charitable Foundation (DDCF) Swedish Child Diabetes Foundation (Barndiabetesfonden) 197064/V50 / Research Council of Norway Western Norway Health Authority Lundbeck Foundation; Lundbeckfonden AdG 293574 / ERC; European Research Council (ERC); European Commission 5-T32-GM007748-33 / US National Institutes of Health (NIH) Training; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA KG Jebsen Foundation City of Kuopio and Social Insurance Institution of Finland U01 DK085501; U01 DK085524; U01 DK085545; U01 DK085584 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA National Heart, Lung, and Blood Institute (NHLBI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) U01-DK085545 / NIH/NIDDK; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Swedish Research Council and the Swedish Heart- Lung Foundation; Swedish Research Council Formas; Swedish Research Council Ministry of Education and Culture of Finland NNF13OC0005637 / Novo Nordisk Fonden; Novo Nordisk Foundation WT098017; WT064890; WT090532; WT090367; WT098381 / Wellcome Trust 2007-201413 / ENGAGE Broad Institute from Pfizer, Inc.
Identifiers: 9938492608331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article