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

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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, Desirée A Douglas, Ravindranath Duggirala & 31 others 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, Rasmus Ribel-Madsen, Oluf Pedersen, Go-T2D Consortium

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.

Original languageEnglish
JournalNature Genetics
Volume46
Issue number4
Pages (from-to)357-63
Number of pages7
ISSN1061-4036
DOIs
Publication statusPublished - Apr 2014

    Research areas

  • Animals, Base Sequence, Blood Glucose, Cation Transport Proteins, Diabetes Mellitus, Type 2, Genetic Association Studies, Genotype, Humans, Ion Transport, Mice, Mice, Knockout, Molecular Sequence Data, Mutation, Missense, Proinsulin, Sequence Analysis, DNA

ID: 117883107