Kidney Week

Abstract: SA-PO543

Genetic Determinants of CKD Progression Among Individuals with Diabetes: The Million Veteran Program

Session Information

• Diabetic Kidney Disease: Pathology, Epidemiology
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Hung, Adriana, VA & Vanderbilt University, Nashville, Tennessee, United States

Adriana Hung,

• Chen, Hua-Chang, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Hua-Chang Chen,

• Chung, Cecilia P., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Cecilia P. Chung,

• Siew, Edward D., Vanderbilt University School of Medicine, Nashville, Tennessee, United States

Edward D. Siew,

• Akwo, Elvis A., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Elvis A. Akwo,

• Giri, Ayush, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ayush Giri,

• Wilson, Otis D., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Otis D. Wilson,

• Edwards, Todd L., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Todd L. Edwards,

• O'Donnell, Christopher Joseph, Boston Veterans Administration, Boston, Massachusetts, United States

Christopher Joseph O'Donnell,

• Wilson, Peter W., Emory University, Atlanta, Georgia, United States

Peter W. Wilson,

• Tao, Ran, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ran Tao,

• Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Cassianne Robinson-Cohen,

Background

The rate of CKD progression among individuals with diabetes varies widely and is incompletely explained by known risk factors. While the genetic determinants of cross-sectional eGFR have been identified, only one small analysis of longitudinal change in eGFR among individuals with CKD has been conducted.

Methods

We performed a genome-wide association study of the relative rate of decline in estimated glomerular filtration rate (eGFR, % decline/year) among individuals with CKD and diabetes participating in the Million Veteran Program. Our study included participants with genetic data available from the MVP second data release, with 351,510 participants from whom 91,523 individuals had type 2 diabetes. Analyses were stratified by race.

Results

There were 28,368 individuals with CKD and diabetes. 21% (n=5904) were of non-hispanic black race /ethnicity. Mean (SD) eGFR at baseline was 51.1 (±8.1) ml/min/1.73m² and median relative kidney function decline was -0.5%/year. Trans-ethnic meta-analysis uncovered 6 SNPs from only one region significantly associated with decline in kidney function. The SNP with the strongest association, rs6047460, lies 45kb upstream of UGT2A1; every additional minor allele was associated with a 1%/year faster decline in eGFR (p=1.1 x 10^-7). Among blacks, we were able to replicate one of four previously identified SNP, rs116356141, which lies between SH2D4B and NRG3 (p=0.03). Among whites, we were able to replicate 2 of 11 SNPs previously associated with incident CKD, rs12917707 (near UMOD, p=6x10^-4) and rs7805747 (intronic for PRKAG2, p=9x10^-3).

Conclusion

Our data suggest that while there is genetic basis for diabetic kidney disease progression, the discovery of the genetic variants involved has been difficult. The etiological heterogeneity of the phenotype could preclude true associations from being detected.

Funding

• Veterans Affairs Support