You are here

Nat Genet DOI:10.1038/ng.2915

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

Publication TypeJournal Article
Year of Publication2014
AuthorsFlannick, 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 AuthorsGo-T2D Consortium, T2D-GENES Consortium
JournalNat Genet
Volume46
Issue4
Pages357-63
Date Published2014 Apr
ISSN1546-1718
KeywordsAnimals, 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.

URLhttp://dx.doi.org/10.1038/ng.2915
DOI10.1038/ng.2915
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24584071?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID24584071
PubMed Central IDPMC4051628
Grant ListR01 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