Abstract: FR-OR063
Phenome-Wide Association Study (PheWAS) of Common Genetic Variants for UMOD in the Million Veteran Program (MVP) Participants
Session Information
- Genetic Diseases and the Kidneys
November 08, 2019 | Location: 144, Walter E. Washington Convention Center
Abstract Time: 04:54 PM - 05:06 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Akwo, Elvis A., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Chen, Hua-Chang, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Siew, Edward D., VA & Vanderbilt University, Nashville, Tennessee, United States
- Tao, Ran, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- O'Donnell, Christopher Joseph, Boston Veterans Administration, Boston, Massachusetts, United States
- Chung, Cecilia P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Hung, Adriana, VA & Vanderbilt University, Nashville, Tennessee, United States
Background
Uromodulin (UMOD) is synthesized exclusively in the kidney and is the most abundant protein in ordinary urine. Common variants for UMOD have been considered an adaptation to protect against urinary tract infections (UTIs). Several GWAS studies of estimated glomerular filtration rate (eGFR) have shown SNPs in UMOD top hits; these variants have also been associated with chronic kidney disease (CKD) progression, ESRD and blood pressure, highlighting shared genetic pathways between these traits. In clinical settings, serum UMOD is increasingly considered a more sensitive indicator of functional kidney mass than filtration markers like eGFR, and has been associated prospectively with cardiovascular outcomes and mortality. Hypertension, vascular calcification and arterial stiffness are hypothesized mechanisms.
Methods
We tested common variants in UMOD and their association with clinically diagnosed phenotypes in a phenome-wide association study (PheWAS) in 188,008 White European Americans from the MVP. Using logistic regression adjusted for sex and 10 principal components, we regressed 1813 phenotypes against our 13 SNPs in models adjusted (and not adjusted) for eGFR.
Results
Eight of the common variants had significant associations for CKD (Table 1), renal failure, hypertensive heart or kidney disease and urinary calculus, and two with UTIs. Other significant associations were with premenstrual syndrome. In the eGFR-adjusted models, the strongest associations were with urinary calculus and disease groupings related to congestive heart failure, including non-hypertensive congestive heart failure.
Conclusion
This PheWAS confirms that UMOD variants are associated with CKD and ESRD. Other observed associations included kidney stones and UTIs. Mendelian Randomization studies of haplotypes for UMOD variants are underway to further elucidate the role of UMOD in vascular health.
Funding
- Veterans Affairs Support