Two GWAS Suggestive-SNVs in the Zinc Transporter 8 Gene Synergistically Influence Insulin Resistance in Type 2 Diabetes

Background: According to the genome-wide association studies (GWASs), zinc transporter 8 ( ZnT8; SLC30A8 ) is among the loci containing variants linked to type 2 diabetes ( T2D ) risk. The variants rs11558471 and rs13266634 are two GWAS-suggestive single nucleotide variations (SNVs), however, their synergistic effects have received less attention, particularly in populations with the high prevalence of diabetes. This study, was thus conducted to determine their synergistic effects on insulin resistance. Methods: A total of 261 subjects were included in this study. Insulin and fasting glucose concentrations were used to calculate the homeostasis model assessment for insulin resistance (HOMA-IR) index. The study variants were genotyped by polymerase chain reaction (PCR)-based restriction analysis. Results: For both variants, the HOMA-IR index is enhanced in the order of risk allele-carrying genotypes (GG<GA<AA for rs11558471 and TT<CT<CC for rs13266634 ). For rs13266634 , in the CT + CC group, this insulin resistance index was significantly higher in T2D patients than in control subjects ( P < 0.001). For rs11558471, in both the GA + AA group and GG genotypes, HOMA-IR was higher in patients than in control subjects; however, only the difference in the GA+AA group was statistically significant ( P < 0.001). Individuals with 3–4 risk alleles had a significantly higher HOMA-IR than that of individuals with 0–2 risk alleles ( P = 0.02). Conclusions: In addition to individual effects on T2D risk, the risk alleles of rs13266634 and rs11558471 seem to collectively work in an additive manner to influence insulin resistance. The combination of their risk alleles may be helpful to diagnose people at high risk for the development of T2D .