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

Flannick, Jason; Thorleifsson, Gudmar; Beer, Nicola L; Jacobs, Suzanne B R; Grarup, Niels; Burtt, Noël P; Mahajan, Anubha; Fuchsberger, Christian; Atzmon, Gil and Benediktsson, Rafn, et al. (2014) In Nature Genetics 46(4). p.357-357
Abstract
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... (More)
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. (Less)
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Nature Genetics
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46
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4
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357 - 357
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Nature Publishing Group
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  • pmid:24584071
  • wos:000334510100011
  • scopus:84897407583
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1546-1718
DOI
10.1038/ng.2915
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English
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04e31993-2f8c-4069-a74a-503f183912ae (old id 4384198)
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@article{04e31993-2f8c-4069-a74a-503f183912ae,
  abstract     = {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.},
  author       = {Flannick, Jason and Thorleifsson, Gudmar and Beer, Nicola L and Jacobs, Suzanne B R and Grarup, Niels and Burtt, Noël P and Mahajan, Anubha and Fuchsberger, Christian and Atzmon, Gil and Benediktsson, Rafn and Blangero, John and Bowden, Don W and Brandslund, Ivan and Brosnan, Julia and Burslem, Frank and Chambers, John and Cho, Yoon Shin and Christensen, Cramer and Douglas, Desiree and Duggirala, Ravindranath and Dymek, Zachary and Farjoun, Yossi and Fennell, Timothy and Fontanillas, Pierre and Forsén, Tom and Gabriel, Stacey and Glaser, Benjamin and Gudbjartsson, Daniel F and Hanis, Craig and Hansen, Torben and Hreidarsson, Astradur B and Hveem, Kristian and Ingelsson, Erik and Isomaa, Bo and Johansson, Stefan and Jørgensen, Torben and Jørgensen, Marit Eika and Kathiresan, Sekar and Kong, Augustine and Kooner, Jaspal and Kravic, Jasmina and Laakso, Markku and Lee, Jong-Young and Lind, Lars and Lindgren, Cecilia M and Linneberg, Allan and Masson, Gisli and Meitinger, Thomas and Mohlke, Karen L and Molven, Anders and Morris, Andrew P and Potluri, Shobha and Rauramaa, Rainer and Ribel-Madsen, Rasmus and Richard, Ann-Marie and Rolph, Tim and Salomaa, Veikko and Segrè, Ayellet V and Skärstrand, Hanna and Steinthorsdottir, Valgerdur and Stringham, Heather M and Sulem, Patrick and Tai, E Shyong and Teo, Yik Ying and Teslovich, Tanya and Thorsteinsdottir, Unnur and Trimmer, Jeff K and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Vaziri Sani, Fariba and Voight, Benjamin F and Wilson, James G and Boehnke, Michael and McCarthy, Mark I and Njølstad, Pål R and Pedersen, Oluf and Groop, Leif and Cox, David R and Stefansson, Kari and Altshuler, David},
  issn         = {1546-1718},
  language     = {eng},
  number       = {4},
  pages        = {357--357},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.},
  url          = {http://dx.doi.org/10.1038/ng.2915},
  volume       = {46},
  year         = {2014},
}