Genome-Wide Survival Study Finds Variants Associated With IgAN Progression

IgA nephropathy (IgAN) has a poor prognosis and often leads to kidney failure, but genetic markers associated with its progression are limited. Xu Linlin and colleagues conducted genome-wide survival analyses and a meta-analysis to help address this gap. They presented findings during ASN Kidney Week 2024 in the poster Genome-Wide Survival Study Identifies Variants Associated with Disease Progression in IgA Nephropathy.

The researchers conducted analyses in two independent cohorts of IgAN patients from China, the PKU-IgAN follow-up cohort (n=1,859) and the TESTING cohort (n=279). They performed genome-wide survival analyses on the two cohorts separately, and selected candidate variants when they had P<1×10-5 in one cohort and P<.05 in the other.

In addition, they conducted functional annotations of candidate variants, expression quantitative trait loci studies, exploration of epigenetic architecture, differential expression of the candidate genes, and the association between genotype and clinical characteristics.

The primary outcome was end-stage renal disease. A variant of SFMBT2 achieved genome-wide significance in the meta-analysis (HR, 3.01; P=8.24×10-9), while SLC8A1 (HR, 1.90; P=2.06×10-7) and MIR548B (HR, 3.19; P=5.04×10-7) were regarded as candidate loci.

The secondary outcome was a combination of ESRD or ≥40% reduction in eGFR after diagnostic kidney biopsy. 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 regarded as candidate loci. SLC8A1, SFMBT2, and FAM19A5 variants were associated with eGFR slope and time-average proteinuria. The risk allele of FAM19A5 was associated with glomerular sclerosis (P=4×10-3) and tubulointerstitial damage (P=.03).

In conclusion, the researchers identified six candidate loci that were significantly associated with IgAN prognosis. If the findings help define the molecular mechanisms of IgAN progression, they could contribute to identification of patients at high risk of disease progression and the development of new therapeutic targets to slow progression.

Source: Linlin X, Zhou X, Lv J, Zhang H. Genome-wide survival study identifies variants associated with disease progression in IgA nephropathy. TH-PO529. Abstract of a poster presented at the American Society of Nephrology Kidney Week 2024; October 24, 2024; San Diego, California.