Authors
Jason Flannick, Gudmar Thorleifsson, Nicola L Beer, Suzanne BR Jacobs, Niels Grarup, Noël P Burtt, Anubha Mahajan, Christian Fuchsberger, Gil Atzmon, Rafn Benediktsson, John Blangero, Don W Bowden, Ivan Brandslund, Julia Brosnan, Frank Burslem, John Chambers, Yoon Shin Cho, Cramer Christensen, Desirée A Douglas, Ravindranath Duggirala, Zachary Dymek, Yossi Farjoun, Timothy Fennell, Pierre Fontanillas, Tom Forsen, Stacey Gabriel, Benjamin Glaser, Daniel F Gudbjartsson, Craig Hanis, Torben Hansen, Astradur B Hreidarsson, Kristian Hveem, Erik Ingelsson, Bo Isomaa, Stefan Johansson, Torben Jørgensen, Marit Eika Jørgensen, Sekar Kathiresan, Augustine Kong, Jaspal Kooner, Jasmina Kravic, Markku Laakso, Jong-Young Lee, Lars Lind, Cecilia M Lindgren, Allan Linneberg, Gisli Masson, Thomas Meitinger, Karen L Mohlke, Anders Molven, Andrew P Morris, Shobha Potluri, Rainer Rauramaa, Rasmus Ribel-Madsen, Ann-Marie Richard, Tim Rolph, Veikko Salomaa, Ayellet V Segrè, Hanna Skärstrand, Valgerdur Steinthorsdottir, Heather M Stringham, Patrick Sulem, E Shyong Tai, Yik Ying Teo, Tanya Teslovich, Unnur Thorsteinsdottir, Jeff K Trimmer, Tiinamaija Tuomi, Jaakko Tuomilehto, Fariba Vaziri-Sani, Benjamin F Voight, James G Wilson, Michael Boehnke, Mark I McCarthy, Pål R Njølstad, Oluf Pedersen, Go-T2D Consortium, T2D-Genes Consortium, Leif Groop, David R Cox, Kari Stefansson, David Altshuler
Publication date
2014/4
Journal
Nature genetics
Volume
46
Issue
4
Pages
357-363
Publisher
Nature Publishing Group US
Description
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 …
Scholar articles
J Flannick, G Thorleifsson, NL Beer, SBR Jacobs… - Nature genetics, 2014