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

Abstract

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, 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, glucose, and proinsulin levels5–7. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk8,9, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts10–15. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention.

Zinc and diabetes

“…Among the variants, the two most common sequences failed to express a stable protein. Thus, SLC30A8 haploinsufficiency leading to a lower expression of the transporter appears from these studies to protect against T2D [73].…”

“…These findings thus uncovered a more complex role for ZnT8 in glucose homeostasis, and in particular in tissue-tissue interactions, than previously thought. Importantly, these complex interactions might contribute to the differences in the impact of genetic deletion of ZnT8 in mice versus reduction in levels (by 50 %) in rare allele carriers [73] or inheritance of risk variants (R325W) [77].…”

“…These findings thus uncovered a more complex role for ZnT8 in glucose homeostasis, and in particular in tissue-tissue interactions, than previously thought. Importantly, these complex interactions might contribute to the differences in the impact of genetic deletion of ZnT8 in mice versus reduction in levels (by 50 %) in rare allele carriers [73] or inheritance of risk variants (R325W) [77].The effects of exposure to a high fat diet as a means of promoting the development of T2D in mice have been studied in global and β cell-specific ZnT8 KO animals [83]. β cell specific null mice displayed similar bodyweights to controls but insulin secretion was impaired and these animals and were glucose-intolerant compared to control littermates.…”

Phenotypic extremes in rare variant study designs

“…As is the case in other analytic settings, the use of phenotypic extremes tends to lead to an overestimate of the effect of the variant and tends to overestimate the proportion of functionally active variants in a region, both of which support the value of population-based samples. 34 However, much larger sample sizes will be needed in order to have the power to detect associations in these instances.…”

10 Years of GWAS Discovery: Biology, Function, and Translation

“…Examples from T2D research highlight the diverse routes by which human genetics can inform translational medicine: (1) the combination of common-variant GWASs and candidate-gene resequencing has demonstrated that loss-of-function mutations in SLC30A8 (MIM: 611145; encoding a zinc transporter expressed in pancreatic islets) are protective for T2D, leading to efforts by several pharma companies to develop ZnT-8 antagonists; 93 (2) the use of genetic variants as instruments that ''simulate'' variation in environmental and biochemical exposures has clarified the extent to which vitamin D intake, early nutrition, circulating lipid levels, and chronic inflammation play causal roles with respect to the development of T2D [94][95][96][97][98] and has defined the relationship between insulin resistance and the distribution of adipose tissue; 99 (3) the identification of genetic variants associated with individual variation in response to commonly used therapeutic agents has refined our understanding of the mechanisms through which those agents operate 100,101 and, in some instances, has led to therapeutic optimization on the basis of genetic and/or clinical phenotype; 102 and (4) the combination of -omic measurements, longitudinal clinical phenotypes, and GWAS data has highlighted sets of molecules (e.g., branched-chain amino acids) that not only are prospectively associated with T2D progression but could also play a causal role in T2D development and thereby provide valuable clinical tools for stratification and prognostication. 103,104 Auto-immune Diseases Variant and Gene Discovery.…”