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

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Flannick, Jason (author)

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

Article/chapterEnglish2014

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2014-03-02
Springer Science and Business Media LLC,2014

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LIBRIS-ID:oai:lup.lub.lu.se:04e31993-2f8c-4069-a74a-503f183912ae
https://lup.lub.lu.se/record/4384198URI
https://doi.org/10.1038/ng.2915DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-225085URI

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Language:English
Summary in:English

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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.

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Thorleifsson, Gudmar (author)
Lind, LarsUppsala universitet,Kardiovaskulär epidemiologi(Swepub:uu)larslind (author)
Jacobs, Suzanne B R (author)
Grarup, Niels (author)
Burtt, Noël P (author)
Mahajan, Anubha (author)
Fuchsberger, Christian (author)
Atzmon, Gil (author)
Benediktsson, Rafn (author)
Blangero, John (author)
Bowden, Don W (author)
Brandslund, Ivan (author)
Brosnan, Julia (author)
Burslem, Frank (author)
Chambers, John (author)
Cho, Yoon Shin (author)
Christensen, Cramer (author)
Douglas, DesireeLund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Cellpatologi, Malmö,Celiac Disease and Diabetes Unit,Lund University Research Groups,Cell Pathology, Malmö(Swepub:lu)cob-ddo (author)
Duggirala, Ravindranath (author)
Dymek, Zachary (author)
Farjoun, Yossi (author)
Fennell, Timothy (author)
Fontanillas, Pierre (author)
Forsén, Tom (author)
Gabriel, Stacey (author)
Glaser, Benjamin (author)
Gudbjartsson, Daniel F (author)
Hanis, Craig (author)
Hansen, Torben (author)
Hreidarsson, Astradur B (author)
Hveem, Kristian (author)
Ingelsson, ErikUppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylär epidemiologi(Swepub:uu)ering425 (author)
Isomaa, Bo (author)
Johansson, Stefan (author)
Jørgensen, Torben (author)
Jørgensen, Marit Eika (author)
Kathiresan, Sekar (author)
Kong, Augustine (author)
Kooner, Jaspal (author)
Kravic, JasminaLund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups(Swepub:lu)med-jik (author)
Laakso, Markku (author)
Lee, Jong-Young (author)
Lind, Lars (author)
Lindgren, Cecilia M (author)
Linneberg, Allan (author)
Masson, Gisli (author)
Meitinger, Thomas (author)
Mohlke, Karen L (author)
Molven, Anders (author)
Morris, Andrew P (author)
Potluri, Shobha (author)
Rauramaa, Rainer (author)
Ribel-Madsen, Rasmus (author)
Richard, Ann-Marie (author)
Rolph, Tim (author)
Salomaa, Veikko (author)
Segrè, Ayellet V (author)
Skärstrand, HannaLund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Celiac Disease and Diabetes Unit,Lund University Research Groups(Swepub:lu)med-hsk (author)
Steinthorsdottir, Valgerdur (author)
Stringham, Heather M (author)
Sulem, Patrick (author)
Tai, E Shyong (author)
Teo, Yik Ying (author)
Teslovich, Tanya (author)
Thorsteinsdottir, Unnur (author)
Trimmer, Jeff K (author)
Tuomi, Tiinamaija (author)
Tuomilehto, Jaakko (author)
Vaziri Sani, FaribaLund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Celiac Disease and Diabetes Unit,Lund University Research Groups(Swepub:lu)fa3255va (author)
Voight, Benjamin F (author)
Wilson, James G (author)
Boehnke, Michael (author)
McCarthy, Mark I (author)
Njølstad, Pål R (author)
Pedersen, Oluf (author)
Groop, LeifLund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups(Swepub:lu)endo-lgr (author)
Cox, David R (author)
Stefansson, Kari (author)
Altshuler, David (author)
Uppsala universitetKardiovaskulär epidemiologi (creator_code:org_t)

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In:Nature Genetics: Springer Science and Business Media LLC46:4, s. 357-3571546-17181061-4036

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By the author/editor: Flannick, Jason; Thorleifsson, Gu ...; Lind, Lars; Jacobs, Suzanne ...; Grarup, Niels; Burtt, Noël P; show more...; Mahajan, Anubha; Fuchsberger, Chr ...; Atzmon, Gil; Benediktsson, Ra ...; Blangero, John; Bowden, Don W; Brandslund, Ivan; Brosnan, Julia; Burslem, Frank; Chambers, John; Cho, Yoon Shin; Christensen, Cra ...; Douglas, Desiree; Duggirala, Ravin ...; Dymek, Zachary; Farjoun, Yossi; Fennell, Timothy; Fontanillas, Pie ...; Forsén, Tom; Gabriel, Stacey; Glaser, Benjamin; Gudbjartsson, Da ...; Hanis, Craig; Hansen, Torben; Hreidarsson, Ast ...; Hveem, Kristian; Ingelsson, Erik; Isomaa, Bo; Johansson, Stefa ...; Jørgensen, Torbe ...; Jørgensen, Marit ...; Kathiresan, Seka ...; Kong, Augustine; Kooner, Jaspal; Kravic, Jasmina; Laakso, Markku; Lee, Jong-Young; Lindgren, Cecili ...; Linneberg, Allan; Masson, Gisli; Meitinger, Thoma ...; Mohlke, Karen L; Molven, Anders; Morris, Andrew P; Potluri, Shobha; Rauramaa, Rainer; Ribel-Madsen, Ra ...; Richard, Ann-Mar ...; Rolph, Tim; Salomaa, Veikko; Segrè, Ayellet V; Skärstrand, Hann ...; Steinthorsdottir ...; Stringham, Heath ...; Sulem, Patrick; Tai, E Shyong; Teo, Yik Ying; Teslovich, Tanya; Thorsteinsdottir ...; Trimmer, Jeff K; Tuomi, Tiinamaij ...; Tuomilehto, Jaak ...; Vaziri Sani, Far ...; Voight, Benjamin ...; Wilson, James G; Boehnke, Michael; McCarthy, Mark I; Njølstad, Pål R; Pedersen, Oluf; Groop, Leif; Cox, David R; Stefansson, Kari; Altshuler, David; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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