Candidate genes for IgA nephropathy in pediatric patients: exome-wide association study

Abstract

IgA nephropathy (IgAN) is an autoimmune disorder that commonly manifests during adolescence. This disease is believed to be a non-monogenic disorder related to variations in multiple genes involved in various biological pathways. We performed the exome-wide association study of 70 children with IgAN confirmed by renal biopsy and 637 healthy donors to identify gene associations responsible for the disease. The HLA allele frequencies between the patients and healthy donors from the bone marrow registry of the Pirogov University were compared. We tested 78,020 gene markers for association, performed the functional enrichment analysis and the transcription factor binding preference detection. We detected 333 genetic variants, employing three inheritance models. The most significant association with the disorder was observed for rs143409664 (PRAG1) in case of the additive and dominant models (PBONF= 1.808 × 10−15and PBONF= 1.654 × 10−15, respectively) and for rs13028230 (UBR3) in case of the recessive model (PBONF = 1.545 × 10−9). Enrichment analysis indicated the strongly overrepresented "immune system" and "kidney development" terms. The HLA-DQA1*01:01:01G allele (P = 0.0076; OR, 2.021 [95% CI, 1.322-3.048]) was significantly the most frequent among IgAN patients. Here we characterized, for the first time, the genetic background of the Russian IgAN patients identifying the risk alleles typical of the population. The most prominent signals were detected in previously undescribed loci.