HORMAD2 – IgA Glomerulonephritis

HORMAD2 (HGNC:28383) has emerged as a candidate risk locus for IgA glomerulonephritis (MONDO_0005342) based on several genome‑wide association studies. Multiple independent cohorts have identified significant associations in the HORMAD2 region, emphasizing its potential role in the immune‐mediated mechanisms underlying IgA deposition in the kidney (PMID:27941131; PMID:31857673).

The genetic evidence indicates that association signals at the HORMAD2 locus have been reproduced across diverse populations. In one study, an intronic variant (rs2412971) was robustly associated with tonsillectomy and, by extension, with increased IgA nephropathy risk, while a separate analysis identified overlapping susceptibility signals for IgA glomerulonephritis and inflammatory bowel disease. Although precise familial segregation data are not available, the large sample sizes involved (e.g., 1464 patients and 12,019 controls in the tonsillectomy study (PMID:27941131) and over 2000 patients in the IBD‐IgAN study (PMID:31857673)) support a moderate genetic contribution.

Given the polygenic nature of IgA glomerulonephritis, the inheritance pattern is best described as complex. No specific HGVS‑formatted coding variant has been provided in these reports; rather, the evidence is based on noncoding risk alleles identified in GWAS. Thus, the variant spectrum remains limited with respect to traditional mutational analysis.

Functional evidence specific to HORMAD2 is currently scarce. Although one study exploring the MTMR3/HORMAD2 locus reported that alterations in gene expression within this region may affect IgA production, direct functional assays for HORMAD2 were not reported. This limits the experimental concordance when compared to the genetic observations (PMID:37414396).

There is also conflicting evidence from related immune defence polymorphism studies. For example, one investigation in IgA vasculitis cohorts did not detect significant genotype differences for several candidate polymorphisms, suggesting that the contribution of HORMAD2 may be context‐dependent or require additional genetic/environmental modifiers (PMID:37685869).

In summary, the convergence of GWAS data across independent cohorts provides a moderately strong genetic basis linking HORMAD2 to IgA glomerulonephritis, even though direct functional validation remains limited. Further studies, including detailed mechanistic and segregation analyses, are essential to solidify the clinical utility of HORMAD2 in diagnostic and therapeutic stratification.

Key Take‑home: HORMAD2 represents a promising risk locus for IgA glomerulonephritis, underscoring its potential incorporation into multifactorial diagnostic frameworks for immune-mediated kidney disease.

References

• International journal of molecular sciences • 2023 • Mucosal Immune Defence Gene Polymorphisms as Relevant Players in the Pathogenesis of IgA Vasculitis? PMID:37685869
• Journal of medical genetics • 2017 • Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy PMID:27941131
• Journal of human genetics • 2020 • Identification of susceptibility locus shared by IgA nephropathy and inflammatory bowel disease in a Chinese Han population PMID:31857673
• Kidney International • 2023 • MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy PMID:37414396

Evidence Based Scoring (AI generated)