SLC30A8: A complex road from association to function

Abstract

One of the more compelling common variants associated with type 2 diabetes (T2D) in the initial wave of genome-wide association studies was a missense variant (rs13266634, p.Trp325Arg) in SLC30A8, a gene that encodes a zinc transporter (ZnT8) expressed primarily in pancreatic islets. This widely replicated association, together with the importance of ZnT8 in the process of zinc transport into insulin secretory granules, provided a potentially straightforward path toward insight into T2D pathogenesis. However, since this initial observation, the path from association to function for SLC30A8 has been far from straightforward. In this chapter, we review (a) the initial genetic evidence that identified variation in SLC30A8 as a risk factor for T2D, (b) the biological function of its protein product (ZnT8), (c) associations between SLC30A8 variation and other diabetes-related intermediate phenotypes, (d) experiments to discern the mechanism whereby perturbation of ZnT8 influences T2D risk, and (e) recent results from large-scale sequencing and genotyping to identify a broader allelic series within SLC30A8. Although both genetic and experimental evidences point to clear link between altered SLC30A8 function and T2D in human populations, the specific mechanism of pathogenesis is still far from clear.