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

Summary, in English

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: Jason Flannick; Gudmar Thorleifsson; Nicola L Beer; Suzanne B R 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; Desiree Douglas; Ravindranath Duggirala; Zachary Dymek; Yossi Farjoun; Timothy Fennell; Pierre Fontanillas; Tom Forsén; 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; Leif Groop; David R Cox; Kari Stefansson; David Altshuler
• Department/s: Celiac Disease and Diabetes Unit; Cell Pathology, Malmö; Translational Muscle Research; EXODIAB: Excellence of Diabetes Research in Sweden
• Publishing year: 2014
• Language: English
• Pages: 357-357
• Publication/Series: Nature Genetics
• Volume: 46
• Issue: 4
• Links: http://www.ncbi.nlm.nih.gov/pubmed/24584071?dopt=Abstract; http://dx.doi.org/10.1038/ng.2915
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Endocrinology and Diabetes
• Status: Published
• Research group: Celiac Disease and Diabetes Unit; Cell Pathology, Malmö; Genomics, Diabetes and Endocrinology
• ISBN/ISSN/Other: ISSN: 1546-1718