Genetic Variation in GUSB Is Associated with Circulating ß-Glucuronidase and Metabolic Traits in Hispanic Postmenopausal Women

Introduction and Objective: β-Glucuronidase, encoded by GUSB, is a lysosomal hydrolase involved in glucuronide metabolism. Recent proteomic studies identified circulating β-glucuronidase as a marker of incident type 2 diabetes, suggesting a link with glucose metabolism. However, whether variation at the GUSB locus contributes to circulating β-glucuronidase and metabolic traits remains unclear. This study examined associations between GUSB genetic variation, serum β-glucuronidase, and metabolic traits in Hispanic postmenopausal women from El Banco por Salud. Methods: Genome-wide genotype data were previously generated in El Banco por Salud, and SNPs within the GUSB locus were extracted for analysis. Serum β-glucuronidase and C-reactive protein (CRP) were measured in 214 postmenopausal women. Genotype-phenotype associations were evaluated using linear regression under an additive genetic model in both unadjusted analyses and models adjusted for age, body mass index, and CRP. Results: The minor allele of an exonic GUSB SNP (rs9530) was associated with lower serum β-glucuronidase (β = -0.30, p = 0.0058), with 12 additional linkage disequilibrium (LD) variants showing similar effects. The same allele was also associated with lower fasting plasma glucose (β = -13.15, p = 0.042) and lower fasting serum insulin (β = -2.37, p = 0.030). Across the LD block, variants associated with lower β-glucuronidase also showed concordant associations with lower fasting plasma glucose, and several with fasting serum insulin or HbA1c. Conclusion: These findings identify a GUSB LD block, represented by rs9530, that influences circulating β-glucuronidase and glucose- and insulin-related phenotypes in Hispanic postmenopausal women. Together with prior proteomic studies linking β-glucuronidase to T2D risk and epidemiologic evidence of higher levels in Hispanic compared with non-Hispanic white women, these results suggest that genetic regulation of GUSB may contribute to pathways involved in glucose homeostasis. Disclosure: D.K. Coletta: None. N. Fatima: None. S.A. Whitman: None. J. Frye: None. S. Ehsani: Advisory Panel; Current; AstraZeneca. J.W. Bea: None. J. Funk: None. Funding: The University of Arizona Cancer Center, Community & Academic Partnership Program Grant