Abstract: PO1646
APOL1 by Second-Gene Interaction on eGFR Among African Americans Without Diabetes: The Million Veteran Program
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Rowan, Bryce, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Tao, Ran, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Lipworth, Loren, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Ikizler, Talat Alp, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- O'Donnell, Christopher Joseph, VA Boston Health Care System Jamaica Plain Campus, Boston, Massachusetts, United States
- Hung, Adriana, VA Tennessee Valley Healthcare System, Nashville, Tennessee, United States
Background
Two high-risk variants in the Apolipoprotein L1 (APOL1) gene are associated with eGFR and a substantial increase in risk of end-stage renal disease (ESRD) among African Americans without diabetes. Not all individuals with high-risk variants develop kidney disease, suggesting that unidentified genetic factors may modify the effects of APOL1.
Methods
We tested interactions between the APOL1 haplotype and single nucleotide polymorphisms (SNPs) from 22 independent loci associated with eGFR among 55,004 African Americans without diabetes in the Million Veteran Program. We used linear regression to investigate multiplicative APOL1*SNP interactions on eGFR at enrollment, adjusting for age, sex, body mass index and the first 5 principal components of ancestry, with Bonferroni-correction for multiple testing (alpha=0.05/22=0.002).
Results
We detected significant interactions between APOL1 high-risk variants and SNPs at two loci (GATM/SPATA5L1 (rs62025168, p-interaction= 0.0012) and UBE2Q2 (rs74024005, p-interaction = 0.0014) (Table). SPATA5L1 is a protein-coding gene with elevated expression in the kidney and previous associations with familial juvenile hyperuricemic nephropathy. UBE2Q2 is also a protein-coding gene with gene expression in the distal kidney tubule of a murine model.
Conclusion
Our results identify two novel APOL1-gene interactions, highlighting that secondary genes may modify the effect of APOL1 on kidney function, which may uncover underlying biological mechanisms and be useful for prevention.
| Number of APOL1 high-risk variants | N | eGFR at enrollment, median (IQR) | ||||||
| Overall | rs62025168 genotype | rs74024005 genotype | ||||||
| AA | AG | GG | AA | AC | CC | |||
| 0-1 | 48,002 | 89 (75,105) | 99 (77,118) | 91 (77,106) | 89 (75, 105) | 91 (76, 105) | 90 (76, 105) | 89 (75, 104) |
| 2 | 7,002 | 87 (72, 103) | 88 (82, 95) | 91 (77,106) | 89 (75, 104) | 85 (72, 101) | 87 (73, 104) | 87 (72, 103) |
| Any | 55,004 | 102 (78, 118) | 92 (77,106) | 91 (76, 105) | 91 (76, 105) | 90 (75, 105) | 89 (74, 104) | |
| p-interaction | 0.0012 | 0.0014 | ||||||
Funding
- NIDDK Support