Loss-of-function variant of SLC30A8 rs13266634 (C > T) protects against type 2 diabetes by stabilizing ZnT8: Insights from epidemiological and computational analyses

Abstract

The loss-of-function variant rs13266634 (C > T) in SLC30A8 has been linked to type-2-diabetes (T2D) susceptibility with conflicting findings. We investigated its role among T2D patients of Bangladesh. The rs13266634 (C > T) variant results in an arginine-to-tryptophan (p.R325W) substitution of SLC30A8-encoded zinc transporter protein, ZnT8. As zinc is crucial for insulin-crystallization for storage, we analyzed its wild-type (WZnT8) and variant (MZnT8) protein conformations via molecular-dynamics (MD) simulations. For the epidemiological analysis, a case-control study was conducted with 90 T2D patients from a diabetic-patient-cohort and 90 gender-matched healthy-controls. Genomic DNA was isolated from blood samples and genotyped by Sanger sequencing. MD simulations, spanning over 100 ns, were executed using GROMACS v2024.4. The homozygous wild CC-genotype was significantly more frequent in T2D patients (66.7 %) than in control (50.0 %) and was increasing T2D risk, with adjusted odds-ratio (OR_adj) of 2.25 under dominant model. Conversely, the polymorphic TT-genotype showed a protective effect, with an OR_adj of 0.196 (95 % CI:0.045–0.850, p = 0.029) in an additive model. MD simulations revealed that MZnT8 variant exhibited higher structural stability, lower flexibility and a more compact conformation than WZnT8. In conclusion, the polymorphic TT-genotype of SLC30A8 plays a protective role in T2D susceptibility. Its protein variant, MZnT8, adopts a stable, compact conformation with lower flexibility, which may decrease zinc transport in insulin secreting granules and impair insulin crystallization. This structural adaptation could enhance glucose-stimulated insulin secretion and ultimately contribute to T2D protection.