Back to Search
Start Over
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
- Source :
- Flannick, J, Thorleifsson, G, Beer, N L, Jacobs, S B R, Grarup, N, Burtt, N P, Mahajan, A, Fuchsberger, C, Atzmon, G, Benediktsson, R, Blangero, J, Bowden, D W, Brandslund, I, Brosnan, J, Burslem, F, Chambers, J, Cho, Y S, Christensen, C, Douglas, D A, Duggirala, R, Dymek, Z, Farjoun, Y, Fennell, T, Fontanillas, P, Forsen, T, Gabriel, S, Glaser, B, Gudbjartsson, D F, Hanis, C, Hansen, T, Hreidarsson, A B, Hveem, K, Ingelsson, E, Isomaa, B, Johansson, S, Jorgensen, T, Jorgensen, M E, Kathiresan, S, Kong, A, Kooner, J, Kravic, J, Laakso, M, Lee, J Y, Lind, L, Lindgren, C M, Linneberg, A, Masson, G, Meitinger, T, Mohlke, K L, Molven, A, Morris, A P, Potluri, S, Rauramaa, R, Ribel-Madsen, R, Richard, A M, Rolph, T, Saloemaa, V, Segre, A V, Skarstrand, H, Steinthorsdottir, V, Stringham, H M, Sulem, P, Tai, E S, Teo, Y Y, Teslovich, T, Thorsteinsdottir, U, Trimmer, J K, Tuomi, T, Tuomilehto, J, Vaziri-Sani, F, Voight, B F, Voight, B F, Boehnke, M, McCarthy, M I, Njolstad, P R, Pedersen, O, Groop, L, Cox, D R, Stefansson, K, Altshuler, D, Go, T D C & Consortium, T D-G 2014, ' Loss-of-function mutations in SLC30A8 protect against type 2 diabetes ', Nature Genetics, vol. 46, no. 4, pp. 357-363 . https://doi.org/10.1038/ng.2915, Nature Genetics; Vol 46, Flannick, J, Thorleifsson, G, Beer, N L, Jacobs, S B R, Grarup, N, Burtt, N P, Mahajan, A, Fuchsberger, C, Atzmon, G, Benediktsson, R, Blangero, J, Bowden, D W, Brandslund, I, Brosnan, J, Burslem, F, Chambers, J, Cho, Y S, Christensen, C, Douglas, D A, Duggirala, R, Dymek, Z, Farjoun, Y, Fennell, T, Fontanillas, P, Forsén, T, Gabriel, S, Glaser, B, Gudbjartsson, D F, Hanis, C, Hansen, T, Hreidarsson, A B, Hveem, K, Ingelsson, E, Isomaa, B, Johansson, S, Jørgensen, T, Jørgensen, M E, Kathiresan, S, Kong, A, Kooner, J, Kravic, J, Laakso, M, Lee, J Y, Lind, L, Lindgren, C M, Linneberg, A, Masson, G, Meitinger, T, Mohlke, K L, Molven, A, Morris, A P, Potluri, S, Rauramaa, R, Ribel-Madsen, R, Richard, A M, Rolph, T, Salomaa, V, Segrè, A V, Skärstrand, H, Steinthorsdottir, V, Stringham, H M, Sulem, P, Tai, E S, Teo, Y Y, Teslovich, T, Thorsteinsdottir, U, Trimmer, J K, Tuomi, T, Tuomilehto, J, Vaziri-Sani, F, Voight, B F, Wilson, J G, Boehnke, M, McCarthy, M I, Njølstad, P R, Pedersen, O, Groop, L, Cox, D R, Stefansson, K & Altshuler, D 2014, ' Loss-of-function mutations in SLC30A8 protect against type 2 diabetes ', Nature Genetics, vol. 46, no. 4, pp. 357-363 . https://doi.org/10.1038/ng.2915
- Publication Year :
- 2014
-
Abstract
- Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/Open 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. 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 info:eu-repo/grantAgreement/EC/FP7/202013
- Subjects :
- Blood Glucose
endocrine system diseases
Genotype
Ion Transport/genetics
Molecular Sequence Data
Mutation, Missense
Genome-wide association study
Blood Glucose/genetics
Zinc Transporter 8
Biology
medicine.disease_cause
Insúlín
Frameshift mutation
Sykursýki
Mutation, Missense/genetics
Mice
Cation Transport Proteins/genetics
Genetics
medicine
Glucose homeostasis
Animals
Humans
Cation Transport Proteins
Genetic Association Studies
Mice, Knockout
Mutation
Ion Transport
SLC30A8
Base Sequence
Genetic heterogeneity
nutritional and metabolic diseases
Sequence Analysis, DNA
Arfgengi
Blóðsykur
3. Good health
Proinsulin/blood
Diabetes Mellitus, Type 2/genetics
Diabetes Mellitus, Type 2
biology.protein
Haploinsufficiency
Proinsulin
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Flannick, J, Thorleifsson, G, Beer, N L, Jacobs, S B R, Grarup, N, Burtt, N P, Mahajan, A, Fuchsberger, C, Atzmon, G, Benediktsson, R, Blangero, J, Bowden, D W, Brandslund, I, Brosnan, J, Burslem, F, Chambers, J, Cho, Y S, Christensen, C, Douglas, D A, Duggirala, R, Dymek, Z, Farjoun, Y, Fennell, T, Fontanillas, P, Forsen, T, Gabriel, S, Glaser, B, Gudbjartsson, D F, Hanis, C, Hansen, T, Hreidarsson, A B, Hveem, K, Ingelsson, E, Isomaa, B, Johansson, S, Jorgensen, T, Jorgensen, M E, Kathiresan, S, Kong, A, Kooner, J, Kravic, J, Laakso, M, Lee, J Y, Lind, L, Lindgren, C M, Linneberg, A, Masson, G, Meitinger, T, Mohlke, K L, Molven, A, Morris, A P, Potluri, S, Rauramaa, R, Ribel-Madsen, R, Richard, A M, Rolph, T, Saloemaa, V, Segre, A V, Skarstrand, H, Steinthorsdottir, V, Stringham, H M, Sulem, P, Tai, E S, Teo, Y Y, Teslovich, T, Thorsteinsdottir, U, Trimmer, J K, Tuomi, T, Tuomilehto, J, Vaziri-Sani, F, Voight, B F, Voight, B F, Boehnke, M, McCarthy, M I, Njolstad, P R, Pedersen, O, Groop, L, Cox, D R, Stefansson, K, Altshuler, D, Go, T D C & Consortium, T D-G 2014, ' Loss-of-function mutations in SLC30A8 protect against type 2 diabetes ', Nature Genetics, vol. 46, no. 4, pp. 357-363 . https://doi.org/10.1038/ng.2915, Nature Genetics; Vol 46, Flannick, J, Thorleifsson, G, Beer, N L, Jacobs, S B R, Grarup, N, Burtt, N P, Mahajan, A, Fuchsberger, C, Atzmon, G, Benediktsson, R, Blangero, J, Bowden, D W, Brandslund, I, Brosnan, J, Burslem, F, Chambers, J, Cho, Y S, Christensen, C, Douglas, D A, Duggirala, R, Dymek, Z, Farjoun, Y, Fennell, T, Fontanillas, P, Forsén, T, Gabriel, S, Glaser, B, Gudbjartsson, D F, Hanis, C, Hansen, T, Hreidarsson, A B, Hveem, K, Ingelsson, E, Isomaa, B, Johansson, S, Jørgensen, T, Jørgensen, M E, Kathiresan, S, Kong, A, Kooner, J, Kravic, J, Laakso, M, Lee, J Y, Lind, L, Lindgren, C M, Linneberg, A, Masson, G, Meitinger, T, Mohlke, K L, Molven, A, Morris, A P, Potluri, S, Rauramaa, R, Ribel-Madsen, R, Richard, A M, Rolph, T, Salomaa, V, Segrè, A V, Skärstrand, H, Steinthorsdottir, V, Stringham, H M, Sulem, P, Tai, E S, Teo, Y Y, Teslovich, T, Thorsteinsdottir, U, Trimmer, J K, Tuomi, T, Tuomilehto, J, Vaziri-Sani, F, Voight, B F, Wilson, J G, Boehnke, M, McCarthy, M I, Njølstad, P R, Pedersen, O, Groop, L, Cox, D R, Stefansson, K & Altshuler, D 2014, ' Loss-of-function mutations in SLC30A8 protect against type 2 diabetes ', Nature Genetics, vol. 46, no. 4, pp. 357-363 . https://doi.org/10.1038/ng.2915
- Accession number :
- edsair.doi.dedup.....d9b7f58ef7f0659b2cc5ed7dd42c8306
- Full Text :
- https://doi.org/10.1038/ng.2915