Genome-Wide Survival Study Identifies Variants Associated with Disease Progression in IgA Nephropathy

Background: IgA nephropathy (IgAN) has a poor prognosis and recent data suggested that almost all of patients may progress to kidney failure within their lifetime. Genetic variations intricately shape disease risks. However, genetic markers associated with the progression of IgA nephropathy have been quite limited. Methods: We performed genome-wide survival analyses in two independent cohorts and meta-analysis, the PKU-IgAN follow-up cohort containing 1859 IgAN patients and the TESTING cohort containing 279 patients from China. The primary outcome was end-stage kidney disease (ESKD), and the secondary outcome was the combination of ESKD or ≥40% reduction in estimated glomerular filtration rate (eGFR) after diagnostic kidney biopsy. Genome-wide survival analyses were performed on the two cohorts separately, and variants were selected as candidate variants when they had P < 1×10-5 in one cohort and P < 0.05 in the other. Functional annotations of candidate variants, expression quantitative trait loci (eQTL) studies, exploration of epigenetic architecture, differential expression of the candidate genes, and the association between genotype and clinical characteristics were conducted. Results: For the primary outcome, a variant of SFMBT2 achieved genome-wide significance in the meta-analysis (HR 3.01, P = 8.24×10-9). Two loci, SLC8A1 (HR 1.90, P = 2.06×10-7) and MIR548B (HR 3.19, P = 5.04×10-7) were considered as the candidate loci. For the secondary outcome, three loci, ESRRG (HR 3.68, P = 7.26×10-8), FAM19A5 (HR 1.76, P = 4.43×10-7), and LINC00583 (HR 3.43, P = 6.07×10-7) were considered as the candidate loci. SLC8A1, SFMBT2, and FAM19A5 variants were also associated with the eGFR slope and time-average proteinuria. In addition, the risk allele of FAM19A5 was associated with the glomerular sclerosis (P = 4×10-3) and the tubulointerstitial damage (P = 0.03). Conclusion: Six candidate loci were significantly associated with prognosis of IgAN. These findings may help characterize molecular mechanisms of progression of IgAN, contributing to the identification of patients at high risk of progression and the development of new therapeutic targets to slow disease progression.