Urinary arsenic metabolism, genetic susceptibility, and their interaction on type 2 diabetes

Growing studies investigated the association of arsenic metabolism with type 2 diabetes (T2D), however, the epidemiological evidence is inconsistent. In addition, the interaction of arsenic metabolism-related genetic risk score (GRS)-arsenic on T2D risk was unclear. The present study aimed to evaluate the association of arsenic metabolism efficiency [inorganic arsenic (iAs)%, monomethylarsonic acid (MMA)%, and dimethylarsinic acid (DMA%)] with T2D risk. Moreover, the relationship of GRS and arsenic metabolism efficiency and the interaction of GRS-arsenic on T2D were investigated. Age- and sex-matched new-onset diabetes case-control study derived from the Dongfeng-Tongji cohort was conducted and 996 pairs participants were included in this study. The leave-one-out approach was used to evaluate the association of arsenic metabolism efficiency with T2D risk. The GRS and weight GRS (wGRS) were calculated based on 79 candidate SNPs. We estimated the relationship of GRS with arsenic metabolism efficiency by linear regression model. The interaction of GRS-arsenic on T2D was assessed by adding a multiplicative interaction term (GRS × arsenic) in the logistic regression models. Urinary iAs% was positively associated with T2D risk, and the OR (95% CI) was 1.06 (1.01, 1.12). MMA% and PMI were negatively associated with T2D risk, and the ORs (95% CI) were 0.87 (0.78, 0.97) and 0.64 (0.47, 0.86), respectively. Urinary DMA, As³⁺, and As⁵⁺ were positively associated with T2D risk. Similar relationships were found between arsenic metabolites and levels of FPG and HbA1c. Moreover, arsenic metabolism-related GRS/wGRS was positively associated with MMA% but negatively associated with DMA%. Genetic predisposition to arsenic metabolism modified the association of inorganic arsenic with T2D risk (P_interaction = 0.033). Taken together, lower arsenic primary metabolism efficiency (higher iAs% and lower MMA%) may increase T2D risk. Genetic predisposition to arsenic metabolism was associated with arsenic metabolism efficiency, and might modify the association of inorganic arsenic with T2D risk.