Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Flannick, J, Thorleifsson, G, Beer, NL, Jacobs, SBR, Grarup, N, Burtt, NP, Mahajan, A, Fuchsberger, C, Atzmon, G, Benediktsson, R, Blangero, J, Bowden, DW, Brandslund, I, Brosnan, J, Burslem, F, Chambers, J, Cho, YShin, Christensen, C, Douglas, DA, Duggirala, R, Dymek, Z, Farjoun, Y, Fennell, T, Fontanillas, P, Forsén, T, Gabriel, S, Glaser, B, Gudbjartsson, DF, Hanis, C, Hansen, T, Hreidarsson, AB, Hveem, K, Ingelsson, E, Isomaa, B, Johansson, S, Jørgensen, T, Jørgensen, MEika, Kathiresan, S, Kong, A, Kooner, J, Kravic, J, Laakso, M, Lee, J-Y, Lind, L, Lindgren, CM, Linneberg, A, Masson, G, Meitinger, T, Mohlke, KL, Molven, A, Morris, AP, Potluri, S, Rauramaa, R, Ribel-Madsen, R, Richard, A-M, Rolph, T, Salomaa, V, Segrè, AV, Skärstrand, H, Steinthorsdottir, V, Stringham, HM, Sulem, P, E Tai, S, Teo, YYing, Teslovich, T, Thorsteinsdottir, U, Trimmer, JK, Tuomi, T, Tuomilehto, J, Vaziri-Sani, F, Voight, BF, Wilson, JG, Boehnke, M, McCarthy, MI, Njølstad, PR, Pedersen, O, Groop, L, Cox, DR, Stefansson, K, Altshuler, D |
Corporate Authors | Go-T2D Consortium, T2D-GENES Consortium |
Journal | Nat Genet |
Volume | 46 |
Issue | 4 |
Pages | 357-63 |
Date Published | 2014 Apr |
ISSN | 1546-1718 |
Keywords | 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 |
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. |
URL | http://dx.doi.org/10.1038/ng.2915 |
DOI | 10.1038/ng.2915 |
Pubmed | |
Alternate Journal | Nat. Genet. |
PubMed ID | 24584071 |
PubMed Central ID | PMC4051628 |
Grant List | R01 DK093757 / DK / NIDDK NIH HHS / United States U01 DK085501 / DK / NIDDK NIH HHS / United States R13 CA124293 / CA / NCI NIH HHS / United States 098017 / / Wellcome Trust / United Kingdom N01 HC095170 / HC / NHLBI NIH HHS / United States 5U01DK085526 / DK / NIDDK NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States U01 DK085524 / DK / NIDDK NIH HHS / United States U01 DK085545 / DK / NIDDK NIH HHS / United States R01 DK072193 / DK / NIDDK NIH HHS / United States U54HG003067 / HG / NHGRI NIH HHS / United States N01 HC095172 / HC / NHLBI NIH HHS / United States N01 HC095171 / HC / NHLBI NIH HHS / United States R01 DK062370 / DK / NIDDK NIH HHS / United States RC2 DK088389 / DK / NIDDK NIH HHS / United States 090532 / / Wellcome Trust / United Kingdom U01 DK085526 / DK / NIDDK NIH HHS / United States U01 DK085584 / DK / NIDDK NIH HHS / United States DK088389 / DK / NIDDK NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States Z01 HG000024 / HG / NHGRI NIH HHS / United States 098381 / / Wellcome Trust / United Kingdom T32 GM007748 / GM / NIGMS NIH HHS / United States |
Nat Genet DOI:10.1038/ng.2915
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
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