rs10010131A in WFS1 is Associated with Elevated Serum Urea in Type 2 Diabetes Patients Treated with SGLT2 Inhibitors

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective agents for type 2 diabetes (T2D) management, yet interindividual variability in response mechanisms remains unclear. This study examined genetic interactions influencing clinical and biochemical outcomes among SGLT2i treated patients. Methods: Data from 13,808 Qatar Biobank participants were analyzed, including 207 propensity score–matched T2D patients stratified into three groups: SGLT2i-treated, metformin monotherapy, and drug-naïve. Significant clinical traits across groups were further assessed for genotype effects within SGLT2i treated patients. Results: Compared with both comparators, SGLT2i-treated individuals showed elevated serum urea (FDR < 0.05). Genetic analysis identified an association between the WFS1 rs10010131 A allele and higher urea levels exclusively in SGLT2i treated patients (β = +0.63 mmol/L per A allele, 95% CI [0.14–1.11], p = 0.012). This variant showed strong linkage disequilibrium (r² = 0.95, D′ = 0.99) with rs6446482 in WFS1. Kidney-specific eQTL data revealed reduced WFS1 expression in A-allele carriers. Discussion: These findings suggest a novel pharmacogenetic interaction between WFS1 rs10010131 and urea regulation under SGLT2i therapy. The observed effect could likely reflect a genotype-related renal adaptive response rather than dysfunction, emphasizing the potential of pharmacogenomic profiling to enhance precision treatment for T2D.