Quantifying APOL1, Human Leukocyte Antigen, and Other Genetic Contributions to Unexplained Kidney Failure

Abstract

Rationale & Objective Unexplained kidney failure (uKF) affects 15% of individuals needing kidney replacement therapy. The lack of a clear diagnosis creates uncertainty about recurrence, familial risk, and trial eligibility. This study sought to identify genetic variants underlying uKF. Study Design Genomic analyses conducted using whole-genome sequencing (WGS) were reviewed by a multidisciplinary team that identified candidate pathogenic variants. A case-control study was implemented for single and structural variants to perform gene-based and polygenic risk score (PRS) association testing. Setting & Participants The study recruited 218 patients with uKF onset before age 50 years from the United Kingdom’s 100,000 Genomes Project. Association analysis was performed in 180 uKF cases that remained unsolved after clinical analysis and constituted the nonmonogenic uKF cohort. 26,373 control subjects were derived from the unaffected relatives of nonrenal probands. Exposures Candidate variants in 537 genes were assessed at a structural and single-variant level in the 218 recruited patients, as were high-risk APOL1 genotypes and PRSs for chronic kidney disease and various glomerular diseases. Outcomes The primary outcomes were establishing a genetic diagnosis and the associations between genetic findings, age, family history, and ancestry. Analytical Approach Candidate variants were reviewed for pathogenicity. Gene-based and structural variant analyses and high-risk APOL1 genotype assessments were performed. PRSs and post hoc HLA associations were also investigated. Results Monogenic diagnoses were made in 38 of 218 patients (17%) using WGS via the clinical arm of the 100,000 Genomes Project. Median uKF onset was at the age of 36 years. Diagnoses were less frequent in patients aged ≥36 years, irrespective of family history. Three older patients without a family history had pathogenic variants in type IV collagen genes. Among individuals with recent African ancestry, high-risk APOL1 genotypes were significantly more common in those with uKF (52% vs 8.4% in those without uKF; P < 0.001). An increased steroid-sensitive nephrotic syndrome PRS was observed in those with high-risk APOL1 genotypes and uKF, partly due to differences at HLA-DQB1∗03:19 . Limitations Potential limitations include the small sizes of subgroups and use of short-read WGS. Conclusions WGS yielded a monogenic diagnosis in 17% of patients with uKF, with no additional solved cases arising from the case-control analysis. These findings underscore APOL1 ’s role in those with recent African ancestry and suggest a genetic architecture distinct from common chronic kidney disease. Plain-Language Summary Our study was motivated by the difficulty in understanding why some people experience kidney failure (KF) without a clear cause. Many patients face uncertainty about their future health and treatment because doctors cannot always find an explanation for their condition. To address this challenge, we examined the complete genetic blueprint of individuals with unexplained KF. We looked for genetic clues that might reveal hidden risks. Our work uncovered specific genetic factors that appear to contribute to KF, especially among people with African heritage. These insights are important because they may help explain why KF happens in some cases and inform personalized diagnosis and treatment.