Loss of function mutations in SLC30A8 protect against type 2 diabetes. J. Flannick1, G. Thorleifsson2, N. L. Beer3, S. B. R. Jacobs1, N. Grarup4, NNF-CBMR Genetics, Go-T2D/T2D-GENES consortia, deCODE genetics, Pfizer-Broad-MGH-Lund T2D project 1) Molecular Biology, Massachusetts General Hospital, Boston, MA; 2) deCODE Genetics, Reykjavik, Iceland; 3) Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, U.K; 4) The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Type 2 diabetes (T2D) affects 300,000,000 people worldwide and is rising in prevalence, but current approaches to prevention only partially delay progression to disease. Loss of function coding mutations that protect against disease risk in human populations (e.g. Nav1.7 and pain, PCSK9 and myocardial infarction) provide in vivo validation of targets for therapeutic development, but none have been previously described for T2D.
Through sequencing and genotyping in ~150,000 individuals from 5 ethnicities, we identified 12 rare protein truncating variants in SLC30A8, a gene that encodes a beta-cell zinc transporter (ZnT8) and that carries a common variant (p.W325R) previously associated with T2D risk, glucose and insulin levels. In aggregate, carriers of these rare variants had a 65% reduction in risk of T2D (p=1.7 x 10-6), and non-diabetic carriers of a frameshift mutation (p.K34SfsX50) in Iceland showed reduced glucose levels (-0.17 s.d., p=4.6x10-4). The two most common variants, each individually associated with protection against T2D, encode unstable forms of ZnT8 and are degraded when expressed in vitro.
Although previous experiments in animal and cellular model systems had led to the hypothesis that reduction in SLC30A8 activity increases T2D risk, these findings from human genetics indicate that haploinsufficiency of SLC30A8 protects against T2D in human populations. These results thus unequivocally establish SLC30A8 as the causal gene responsible for the common variant association signal, phase the directional relationship between gene activity and T2D risk, and illustrate the value of human population data for the generation of therapeutic hypotheses.
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