Candidate Genes for IgA Nephropathy in Pediatric Patients: Exome-Wide Association Study

Abstract

IgA nephropathy (IgAN) is an autoimmune disorder which is believed to be non-monogenic. We performed an exome-wide association study of 70 children with IgAN and 637 healthy donors. The HLA allele frequencies were compared between the patients and healthy donors from the bone marrow registry of the Pirogov University. We tested 78,020 gene markers for association and performed functional enrichment analysis and transcription factor binding preference detection. We identified 333 genetic variants, employing three inheritance models. The most significant association with the disorder was observed for rs143409664 (PRAG1) in the case of the additive and dominant models (PBONF = 1.808 × 10−15 and PBONF = 1.654 × 10−15, respectively), and for rs13028230 (UBR3) in the 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 Russian IgAN patients, identifying the risk alleles typical of the population. The most important signals were detected in previously undescribed loci.

Trio-Based Exome Sequencing and High-Resolution HLA Typing in Families of Patients with Autoimmune Adrenal Insufficiency and Autoimmune Polyglandular Syndrome

“…Genes from the HPO 'Autoimmunity' panel HP:0002960 [24], excluding HLA genes, and our custom panel based on literature data (Table S8) were analyzed. A group of 637 healthy volunteers, who had undergone whole-exome sequencing in a previous study [53], was utilized as controls. Before performing the transmission disequilibrium test (TDT), we removed 1790 variants from the vcf file due to genotyping quality less than 95%.…”