Phenome-Wide Association Study of UMOD Gene Variants and Differential Associations With Clinical Outcomes Across Populations in the Million Veteran Program a Multiethnic Biobank

INTRODUCTION: Common variants in the UMOD gene are considered an evolutionary adaptation against urinary tract infections (UTIs) and have been implicated in kidney stone formation, chronic kidney disease (CKD), and hypertension. However, differences in UMOD variant-phenotype associations across population groups are unclear. METHODS: We tested associations between UMOD/PDILT variants and up to 1528 clinical diagnosis codes mapped to phenotype groups in the Million Veteran Program (MVP), using published phenome-wide association study (PheWAS) methodology. Associations were tested using logistic regression adjusted for age, sex, and 10 principal components of ancestry. Bonferroni correction for multiple comparisons was applied. RESULTS: Among 648,593 veterans, mean (SD) age was 62 (14) years; 9% were female, 19% Black, and 8% Hispanic. In White patients, the rs4293393 UMOD risk variant associated with increased uromodulin was associated with increased odds of CKD (odds ratio [OR]: 1.22, 95% CI: 1.20–1.24, P = 5.90 × 10(−111)), end-stage kidney disease (OR: 1.17, 95% CI: 1.11–1.24, P = 2.40 × 10(−09)), and hypertension (OR: 1.03, 95% CI: 1.05–1.05, P = 2.11 × 10(−06)) and significantly lower odds of UTIs (OR: 0.94, 95% CI: 0.92–0.96, P = 1.21 × 10(−10)) and kidney calculus (OR: 0.85, 95% CI: 0.83–0.86, P = 4.27 × 10(−69)). Similar findings were observed across UMOD/PDILT variants. The rs77924615 PDILT variant had stronger associations with acute cystitis in White female (OR: 0.73, 95% CI: 0.59–0.91, P = 4.98 × 10(−03)) versus male (OR: 0.99, 95% CI: 0.89–1.11, P = 8.80 × 10(−01)) (P interaction = 0.01) patients. In Black patients, the rs77924615 PDILT variant was significantly associated with pyelonephritis (OR: 0.65, 95% CI: 0.54–0.79, P = 1.05 × 10(−05)), whereas associations with UMOD promoter variants were attenuated. CONCLUSION: Robust associations were observed between UMOD/PDILT variants linked with increased uromodulin expression and lower odds of UTIs and calculus and increased odds of CKD and hypertension. However, these associations varied significantly across ancestry groups and sex.