Study identifies novel IgAN loci through pleiotropy

IgA nephropathy (IgAN) is a prevalent form of primary glomerulonephritis characterized by the deposition of IgA in the glomerular mesangium, leading to a spectrum of histopathological lesions and a variable clinical course that can progress to end-stage renal disease in a significant proportion of patients. This condition poses a substantial healthcare burden, with a marked geographical variation in prevalence, being most common in Asian populations. Genetic and environmental factors are implicated in the pathogenesis of IgAN, and while several genome-wide association studies (GWAS) have identified susceptibility loci, the genetic architecture remains largely undefined.

This integrative genome-wide analysis focuses on identifying susceptibility loci and relevant cell types for IgAN in Han Chinese individuals. The researchers conducted a large-scale GWAS meta-analysis involving 3616 cases and 10,417 controls, leveraging individual genotyping data from published Han Chinese IgAN GWAS and imputing samples with an Asian whole-genome sequencing reference panel. The meta-analysis, adjusted for population structure, identified six independent IgAN loci, including a novel locus at 4p14. Enrichment analysis based on GWAS summary statistics revealed significant tissue specificity for IgAN in whole blood and PMA-I-stimulated CD4+CD25-IL17+ Th17 cells, highlighting the role of mucosal immunity and Th17 cells in IgAN pathogenesis.

The study further employed the genetic analysis incorporating pleiotropy and annotation (GPA) method to discover additional IgAN susceptibility loci by leveraging shared pleiotropy with inflammatory bowel disease (IBD) and asthma, as well as genomic functional annotations from relevant cell types. This approach identified seven novel loci associated with IgAN, six of which were discovered through integrative analysis with GWAS summary statistics of IBD and asthma. The findings suggest a shared etiology among IgAN, IBD, and asthma, potentially involving common genetic mechanisms related to immune dysregulation, particularly in the context of mucosal immunity.

The clinical relevance of these genetic findings was explored by examining the association of lead variants at the novel loci with clinical phenotypes in IgAN patients. The protective allele at one locus was associated with lower serum IgA levels, and another was correlated with milder proteinuria, underscoring the potential for these genetic variants to influence disease severity and progression. Additionally, a polygenic risk score (PRS) based on identified loci was significantly associated with increased proteinuria and lower estimated glomerular filtration rate (eGFR), indicating the potential utility of PRS in predicting IgAN prognosis.

Functional investigation of the novel loci and variants was conducted using expression quantitative trait loci (eQTL) analysis and functional annotation, revealing potential regulatory roles and associations with immune-related diseases. For instance, variants near UBE2L3 and TRAF3 were associated with the expression of these genes in immune cells, linking them to immune response pathways implicated in autoimmune diseases.

In conclusion, this comprehensive analysis of IgAN in Han Chinese individuals has expanded the understanding of the genetic susceptibility and molecular mechanisms underlying IgAN. By identifying novel susceptibility loci, relevant cell types, and functional implications, the study contributes to the growing body of knowledge on the genetic basis of IgAN and provides a foundation for future research into targeted therapies and precision medicine approaches for this disease.