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

• Published in: Nature genetics Vol. 46; no. 4; pp. 357 - 363
• Main Authors: Flannick, Jason, Thorleifsson, Gudmar, Beer, Nicola L, Jacobs, Suzanne B R, Grarup, Niels, Burtt, Noël P, Mahajan, Anubha, Fuchsberger, Christian, Atzmon, Gil, Benediktsson, Rafn, Blangero, John, Bowden, Don W, Brandslund, Ivan, Brosnan, Julia, Burslem, Frank, Chambers, John, Cho, Yoon Shin, Christensen, Cramer, Douglas, Desirée A, Duggirala, Ravindranath, Dymek, Zachary, Farjoun, Yossi, Fennell, Timothy, Fontanillas, Pierre, Forsén, Tom, Gabriel, Stacey, Glaser, Benjamin, Gudbjartsson, Daniel F, Hanis, Craig, Hansen, Torben, Hreidarsson, Astradur B, Hveem, Kristian, Ingelsson, Erik, Isomaa, Bo, Johansson, Stefan, Jørgensen, Torben, Jørgensen, Marit Eika, Kathiresan, Sekar, Kong, Augustine, Kooner, Jaspal, Kravic, Jasmina, Laakso, Markku, Lee, Jong-Young, Lind, Lars, Lindgren, Cecilia M, Linneberg, Allan, Masson, Gisli, Meitinger, Thomas, Mohlke, Karen L, Molven, Anders, Morris, Andrew P, Potluri, Shobha, Rauramaa, Rainer, Ribel-Madsen, Rasmus, Richard, Ann-Marie, Rolph, Tim, Salomaa, Veikko, Segrè, Ayellet V, Skärstrand, Hanna, Steinthorsdottir, Valgerdur, Stringham, Heather M, Sulem, Patrick, Tai, E Shyong, Teo, Yik Ying, Teslovich, Tanya, Thorsteinsdottir, Unnur, Trimmer, Jeff K, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Vaziri-Sani, Fariba, Voight, Benjamin F, Wilson, James G, Boehnke, Michael, McCarthy, Mark I, Njølstad, Pål R, Pedersen, Oluf, Groop, Leif, Cox, David R, Stefansson, Kari, Altshuler, David
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2014; Nature Publishing Group
• Subjects: 45/23; 631/208/205; 631/208/514; 692/699/2743/137/773; Agriculture; Animal Genetics and Genomics; Animals; Base Sequence; Basic Medicine; Biomedicine; Blood Glucose - genetics; Cancer Research; Cation Transport Proteins - genetics; Clinical Medicine; Diabetes; Diabetes Mellitus, Type 2 - genetics; Endocrinology and Diabetes; Endokrinologi och diabetes; Gene Function; Gene mutations; Genetic aspects; Genetic Association Studies; Genetic research; Genetic susceptibility; Genetics; Genomes; Genotype; Genotype & phenotype; Heterogeneity; Human Genetics; Humans; Identification and classification; Ion Transport - genetics; Klinisk medicin; letter; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Knockout; Molecular Sequence Data; Mutation; Mutation, Missense - genetics; Prevention; Proinsulin - blood; Proteins; Sequence Analysis, DNA; Studies; Type 2 diabetes; Zinc Transporter 8
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2915

David Altshuler and colleagues report genotyping or sequencing of ∼150,000 individuals from several population-based cohorts, identifying 12 rare protein-truncating variants in SLC30A8 , encoding a pancreatic islet zinc transporter. Carriers of these rare protein-truncating variants in SLC30A8 show reduced risk of type 2 diabetes and reduced glucose levels. Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets 1 , 2 , 3 , 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) 4 and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels 5 , 6 , 7 . 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 8 , 9 , and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts 10 , 11 , 12 , 13 , 14 , 15 . 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.