Journal
NATURE GENETICS
Volume 46, Issue 4, Pages 357-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2915
Keywords
-
Categories
Funding
- US National Institutes of Health (NIH) Training [5-T32-GM007748-33]
- Doris Duke Charitable Foundation [2006087]
- Fulbright Diabetes UK Fellowship [BDA 11/0004348]
- Broad Institute from Pfizer, Inc.
- NIH [U01 DK085501, U01 DK085524, U01 DK085545, U01 DK085584]
- Swedish Research Council [Dnr 521-2010-3490, Dnr 349-2006-237]
- European Research Council (ERC) [GENETARGET T2D, GA269045]
- ENGAGE [2007-201413]
- CEED3 [2008-223211]
- Sigrid Juselius Foundation
- Folkh lsan Research Foundation
- ERC [AdG 293574]
- Research Council of Norway [197064/V50]
- KG Jebsen Foundation
- University of Bergen
- Western Norway Health Authority
- Lundbeck Foundation
- Novo Nordisk Foundation
- Wellcome Trust [WT098017, WT064890, WT090532, WT090367, WT098381]
- Uppsala University
- Swedish Research Council and the Swedish Heart- Lung Foundation
- Academy of Finland [124243, 102318, 123885, 139635]
- Finnish Heart Foundation
- Finnish Diabetes Foundation, Tekes [1510/31/06]
- Commission of the European Community [HEALTH-F2-2007-201681]
- Ministry of Education and Culture of Finland
- European Commission Framework Programme 6 Integrated Project [LSHM-CT-2004-005272]
- City of Kuopio and Social Insurance Institution of Finland
- Finnish Foundation for Cardiovascular Disease
- NIH/NIDDK [U01-DK085545]
- National Heart, Lung, and Blood Institute (NHLBI)
- National Institute on Minority Health and Health Disparities [N01 HC-95170, N01 HC-95171, N01 HC-95172]
- European Union Seventh Framework Programme, DIAPREPP
- Swedish Child Diabetes Foundation (Barndiabetesfonden)
- [5U01DK085526]
- [DK088389]
- [U54HG003067]
- [R01DK072193]
- [R01DK062370]
- [Z01HG000024]
- National Institute for Health Research [NF-SI-0611-10099] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0005637] Funding Source: researchfish
- Academy of Finland (AKA) [102318] Funding Source: Academy of Finland (AKA)
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available