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

Elvis A Akwo; Hua-Chang Chen; Ge Liu; Jefferson L Triozzi; Ran Tao; Zhihong Yu; Cecilia P Chung; Ayush Giri; T Alp Ikizler; C Michael Stein; Edward D Siew; QiPing Feng; Cassianne Robinson-Cohen; Adriana M Hung; VA Million Veteran Program

doi:10.1016/j.ekir.2022.05.011

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

Kidney Int Rep. 2022 May 18;7(8):1802-1818. doi: 10.1016/j.ekir.2022.05.011. eCollection 2022 Aug.

Authors

Elvis A Akwo^{1

2

3}, Hua-Chang Chen⁴, Ge Liu⁵, Jefferson L Triozzi¹, Ran Tao^{4

6}, Zhihong Yu⁴, Cecilia P Chung^{3

6

7

8}, Ayush Giri^{6

9

10}, T Alp Ikizler^{1

2

3}, C Michael Stein⁸, Edward D Siew^{1

2

3}, QiPing Feng⁸, Cassianne Robinson-Cohen^{1

2

3}, Adriana M Hung^{1

2

3}; VA Million Veteran Program

Affiliations

¹ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Vanderbilt Center for Kidney Disease, Nashville, Tennessee, USA.
³ VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
⁴ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁵ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁶ Vanderbilt Genetics Institute, Nashville, Tennessee, USA.
⁷ Division of Rheumatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁸ Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁹ Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁰ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Abstract

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.

Keywords: genetic renal disease; hypertension; kidney stones; multiethnic; urinary tract infection; uromodulin.

Grants and funding

I01 CX001897/CX/CSRD VA/United States