| Literature DB >> 24584071 |
Jason Flannick1, Gudmar Thorleifsson2, Nicola L Beer3, Suzanne B R Jacobs4, Niels Grarup5, Noël P Burtt4, Anubha Mahajan6, Christian Fuchsberger7, Gil Atzmon8, Rafn Benediktsson9, John Blangero10, Don W Bowden11, Ivan Brandslund12, Julia Brosnan13, Frank Burslem14, John Chambers15, Yoon Shin Cho16, Cramer Christensen17, Desirée A Douglas18, Ravindranath Duggirala10, Zachary Dymek4, Yossi Farjoun4, Timothy Fennell4, Pierre Fontanillas4, Tom Forsén19, Stacey Gabriel4, Benjamin Glaser20, Daniel F Gudbjartsson2, Craig Hanis21, Torben Hansen22, Astradur B Hreidarsson9, Kristian Hveem23, Erik Ingelsson24, Bo Isomaa25, Stefan Johansson26, Torben Jørgensen27, Marit Eika Jørgensen28, Sekar Kathiresan29, Augustine Kong2, Jaspal Kooner30, Jasmina Kravic31, Markku Laakso32, Jong-Young Lee33, Lars Lind34, Cecilia M Lindgren35, Allan Linneberg36, Gisli Masson2, Thomas Meitinger37, Karen L Mohlke38, Anders Molven39, Andrew P Morris40, Shobha Potluri41, Rainer Rauramaa42, Rasmus Ribel-Madsen5, Ann-Marie Richard13, Tim Rolph13, Veikko Salomaa43, Ayellet V Segrè44, Hanna Skärstrand18, Valgerdur Steinthorsdottir2, Heather M Stringham7, Patrick Sulem2, E Shyong Tai45, Yik Ying Teo46, Tanya Teslovich7, Unnur Thorsteinsdottir47, Jeff K Trimmer13, Tiinamaija Tuomi48, Jaakko Tuomilehto49, Fariba Vaziri-Sani18, Benjamin F Voight50, James G Wilson51, Michael Boehnke7, Mark I McCarthy52, Pål R Njølstad53, Oluf Pedersen5, Leif Groop54, David R Cox41, Kari Stefansson47, David Altshuler55.
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.Entities:
Mesh：
Substances：
Year: 2014 PMID： 24584071 PMCID： PMC4051628 DOI： 10.1038/ng.2915
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330