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Kidney Week

Abstract: PO1652

Genome-Wide Analyses Provide Insights into the Genetic Architecture of Kidney Function and CKD Among Hispanics in the Million Veteran Program

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Akwo, Elvis A., VUMC, Nashville, Tennessee, United States
  • Robinson-Cohen, Cassianne, VUMC, Nashville, Tennessee, United States
  • Rowan, Bryce, VUMC, Nashville, Tennessee, United States
  • Siew, Edward D., Nashville VAMC, Nashville, Tennessee, United States
  • Tao, Ran, VUMC, Nashville, Tennessee, United States
  • O'Donnell, Christopher Joseph, VA Boston Health Care System Jamaica Plain Campus, Boston, Massachusetts, United States
  • Hung, Adriana, Nashville VAMC, Nashville, Tennessee, United States
Background

Hispanics (HAs) have a higher risk of progressing to end-stage renal disease (ESRD) than non-Hispanic European Americans. Genetic variants influencing kidney function have been identified through genome-wide association studies (GWAS) of CKD and ESRD, as well as estimated glomerular filtration rate (eGFR), however, small sample sizes have stalled discovery in the Hispanic population.

Methods

We performed a GWAS of eGFR in 32,821 Hispanics from the Million Veteran Program (MVP); eGFR was estimated using the CKD EPI equation with IDMS calibrated creatinine. Patients on dialysis, transplant recipients, or with BMI <18 kg/m2 were excluded. eGFR was regressed on to common genetic variants (minor allele frequency > 1%) imputed to the 1000 Genomes reference panel adjusted for age, sex, BMI, and the top ten principal components. Analyses were performed by strata of diabetes, estimates from which were aggregated with fixed-effects meta-analysis.

Results

A total of 397 SNPs representing 8 loci exceeded genome-wide significance. The most significant association was at a previously known locus, SPATA5L/GATM on chromosome 15 (p-value =3.78Ex10 -21). Two novel loci were detected. One in SLC30A4 (rs2643718 p-value= 4.51x10-15) a protein-coding gene for zinc transmembrane transporter, and another one on LNC00972 (rs62489732 p-value= 2.64x10-8). Other previously reported signals in the European American population for kidney phenotypes were also found with genome-wide significance : UMOD/PDILT (rs71149135 p-value =1.18 x -9 ), PRKAG2 (rs10224210 p-value 1.99= x10 -12 ), UNCX ( rs12702509 p-value =2.22 x10 -9 ), SLC34A1 (rs3812036 p-value = 1.29x10-9 ) and ALMS1P1 (rs12713788 p-value =4.14 10-8). . Several additional important CKD loci were associated with kidney function at p-values below the genome-wide threshold including: APOL1 (rs6029573 p=2.98 10-6), TPRKB (rs35805651 5.49 10-7), SHROOM3 (rs60529470 p=1.36 10-6). Five of the variants that reached genome-wide significance were exonic variants.

Conclusion

Our study results emphasize the transethnic nature of genetic variation contributing to kidney function. Overall, this is the largest GWAS of eGFR in Hispanics to date, which replicates previously identified loci in tranethnic analysis and detects two novel loci in Hispanics.

Funding

  • Veterans Affairs Support