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Abstract: SA-OR26

Genome-wide Analyses Provide Insights into the Architecture of Kidney Function and CKD in African Americans in the Million Veteran Program (MVP)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Rowan, Bryce, Nashville VAMC, Nashville, Tennessee, United States
  • Robinson-Cohen, Cassianne, Nashville VAMC, Nashville, Tennessee, United States
  • Akwo, Elvis A., VUMC, Nashville, Tennessee, United States
  • Chen, Hua-Chang, VUMC, Nashville, Tennessee, United States
  • Tao, Ran, VUMC, Nashville, Tennessee, United States
  • Chung, Cecilia P., VUMC, Nashville, Tennessee, United States
  • Kovesdy, Csaba P., Memphis VA, Memphis, Tennessee, United States
  • Susztak, Katalin, Penn Medicine, Philadelphia, Pennsylvania, United States
  • O'Donnell, Christopher Joseph, Boston VA, Nahsville, Massachusetts, United States
  • Siew, Edward D., Nashville VAMC, Nashville, Tennessee, United States
  • Hung, Adriana, Nashville VAMC, Nashville, Tennessee, United States
Background

End-stage kidney disease (ESKD) incidence rates for African Americans are more than 3 times higher than for European-Americans. This disparity has been only partly explained by known determinants of ESKD and the presence of high-risk APOL1 variants. The identification of “second hit” triggers may explain kidney outcome disparities observed in African Americans.

Methods

We performed a GWAS of eGFR among 84,544 African Americans from the MVP at or closest to enrollment. Exclusion criteria were: dialysis, kidney transplant, and BMI<18. We evaluated the association of common (minor allele frequency > 1%) SNPs with linear eGFR (by CKD-EPI equation), adjusted for age, sex, BMI, and the top ten principal components of ancestry. Analyses were performed by strata of diabetes and estimates were aggregated with fixed-effects meta-analysis.

Results

We identified 2,275 SNPs in 22 independent loci associated with eGFR (p<5x10-8). The SNP with the strongest signals replicated previously detected associations at SPATA5L1/GATM (rs2486272, p = 1.7 x 10-60). Of these, 19 represented previously reported loci from GWAS of kidney function or CKD. Known CKD genes from case-control studies such as APOL1 (rs73885319 p=9.09x10-28) were included in the known loci. Three were novel loci for the association with kidney function in African Americans. Of the novel variants, we discovered SNPs in ABCA1 (rs10991574 p = 2.97x10-8) associated with accelerated atherosclerosis and lipid metabolism through PPAR alpha , PIK3AP1(rs556476 p = 3.1 x10-09) associated with leukocyte count and BLNK(rs9664029 p=2.49 10-8) associated with colorectal adenoma. Some of the strongest signals previously reported for kidney phenotypes included: DAB2 (rs2542713 p=1.5 x 10-8), OCT2 (rs2279463, p=1.98 10-14), UNCX (rs62435145 p=1.97 10-12) and PRKAG2 (rs10253736 p=3.0x10-8 ). 70 SNPs were exonic variants overall. SNPs within UMOD/PDILT, the top hits for kidney function GWAS and CKD progression among European-Americans, did not reach genome-wide (p=9.19x10-8) significance.

Conclusion

In this large GWAS of eGFR among African Americans to date, we replicate over 19 previously identified loci, identify 3 novel loci associate with kidney function.

Funding

  • Veterans Affairs Support