Loss-of-function mutations in <i>SLC30A8</i> protect against type 2 diabetes



Flannick, Jason, Thorleifsson, Gudmar, Beer, Nicola L, Jacobs, Suzanne BR, Grarup, Niels, Burtt, Noel P, Mahajan, Anubha, Fuchsberger, Christian, Atzmon, Gil, Benediktsson, Rafn
et al (show 70 more authors) (2014) Loss-of-function mutations in <i>SLC30A8</i> protect against type 2 diabetes. NATURE GENETICS, 46 (4). 357-+.

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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.

Item Type: Article
Uncontrolled Keywords: Go-T2D Consortium, T2D-GENES Consortium, Animals, Mice, Knockout, Humans, Mice, Diabetes Mellitus, Type 2, Proinsulin, Blood Glucose, Cation Transport Proteins, Sequence Analysis, DNA, Ion Transport, Base Sequence, Genotype, Mutation, Missense, Molecular Sequence Data, Genetic Association Studies, Zinc Transporter 8
Depositing User: Symplectic Admin
Date Deposited: 16 Jan 2015 09:21
Last Modified: 05 Oct 2023 08:57
DOI: 10.1038/ng.2915
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/2004967