Kidney Week

Abstract: TH-PO0627

UBDb Modifies the Association of APOL1 Risk Alleles with Kidney Failure in People with HIV

Session Information

• Genetic Diseases of the Kidneys: Complex Kidney Traits
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits

Authors

• Fisher, Molly, Albert Einstein College of Medicine, Bronx, New York, United States

Molly Fisher, DO, MS, FASN

• Nicoletti, Paola, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Paola Nicoletti, PhD

• Peter, Inga, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Inga Peter

• Crane, Heidi M, University of Washington, Seattle, Washington, United States

Heidi M Crane, MD, MPH

• Wyatt, Christina M., Duke University School of Medicine, Durham, North Carolina, United States

Christina M. Wyatt, MD

• Ross, Michael J., Albert Einstein College of Medicine, Bronx, New York, United States

Michael J. Ross, MD, FASN

Group or Team Name

• On behalf of the CFAR Network of Integrated Clinical Systems.

Background

HIV-associated nephropathy (HIVAN) is the kidney disease most strongly linked to APOL1 high-risk genotypes. Ubiquitin D (UBD) is a crucial mediator of kidney injury in HIVAN and the UBD locus is associated with altered APOL1 expression. A UBD haplotype (UBD^b) comprising 4 missense SNPs in absolute linkage disequilibrium is most frequent in persons of African ancestry. We examined whether UBD^b modifies the association of APOL1 risk alleles with kidney failure in people with HIV (PWH).

Methods

We conducted a case-control study of PWH in CNICS, a multicenter US HIV cohort. Cases (n=199) had CKD stage 5 defined by sustained eGFR <15 mL/min/1.73m² for >90 days and controls (n=921) had eGFR ≥90ml/min/1.73m² during follow up. We evaluated 3 UBD^b SNPs (rs7757931, rs2076486, rs2076484). We compared UBD^b allele frequency in cases vs controls by APOL1 risk allele count. Logistic regression tested whether UBD^b modified the association of APOL1 risk alleles with kidney failure. Models were stratified by UBD^b and adjusted for age, sex, comorbidities, and HIV RNA. To minimize confounding by population stratification, we restricted analyses to PWH with >70% African ancestry.

Results

Among 1,120 PWH, mean age was 38.8 years, 30.8% were women, 46.8% carried 1 and 12.5% carried 2 APOL1 risk alleles, respectively. In cases, UBD^b allele frequency was 39.7%, 50%, and 50.6% in individuals with 0, 1, or 2 APOL1 risk alleles (G1 or G2), respectively. In controls, corresponding allele frequencies were 46.9%, 44.4%, and 41.1%. In stratified models, APOL1 risk alleles were more strongly associated with kidney failure in UBD^b carriers, who had over twice the odds of kidney failure vs non-carriers at each APOL1 risk level (aORs [95% CI]: 2.97 [1.69–5.41] vs 1.01 [0.41–2.46] for 1 allele; 18.33 [9.67–34.76] vs 7.42 [2.94–18.77] for 2 alleles; Figure).

Conclusion

In African American PWH, associations of APOL1 risk alleles with kidney failure are stronger in the presence of UBD^b, suggesting that it may interact with APOL1 to promote kidney failure.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025gexgsnyz