Quantifying the genetic contributions in unexplained kidney failure reveals APOL1-HLA interaction.

BackgroundUnexplained kidney failure (uKF) affects 15% of individuals requiring kidney replacement therapy. Absence of a diagnosis creates uncertainty around recurrence after transplantation, familial risk, and participation in therapeutic trials. Whole genome sequencing (WGS) was used to identify genetic variants contributing to uKF. Methods218 patients who presented with uKF < 50 years old were recruited to the UKs 100,000 Genomes Project. Candidate variants in 183 genes were reviewed for pathogenicity by a multidisciplinary team. Gene-based association testing, structural variant analyses, and assessment of high-risk APOL1 genotypes were performed. Polygenic risk scores (PRS) were calculated for chronic kidney disease (CKD), and various glomerulonephritides. HLA associations in those with APOL1 high-risk genotype were also investigated. ResultsA positive genetic diagnosis was made in 17% (38/218) of patients. The median age of uKF onset was 36 years. Fewer genetic diagnoses were found in those aged [&ge;] 36 years compared to younger individuals, both with (11% vs. 35%, P=0.03) and without (5% vs. 19%, P=0.05) a family history. Three patients [&ge;] 36 years without a family history had pathogenic variants in type IV collagen genes. High-risk APOL1 genotypes were enriched in patients with recent African ancestry (52% vs 8.4%, P=5.97x10-8). Dividing the uKF cohort by subsequent identification of monogenic diagnosis, High-risk APOL1 genotype, or neither, we found that the SSNS PRS was higher in those with High-risk APOL1 (P=0.048), driven by differences at HLA-DQB1*03:19 (P=0.001). ConclusionsThese findings estimate the likelihood of a genetic diagnosis using WGS in uKF patients, showing fewer diagnoses in older patients without a family history. APOL1 contributes significantly to uKF in those with recent African ancestry, potentially interacting with HLA-DQB1. The lack of PRS signal for CKD suggests distinct biology between uKF and more common causes of CKD.