Genome-Wide Association Study of Antiglomerular Basement Membrane Disease

Background: Anti-glomerular basement membrane (GBM) disease is a rare small vessel vasculitis caused by circulating antibodies directed against GBM, with an incidence of 1-2 cases per million population worldwide. Our study aimed to identify genetic loci associated with the increased risk of anti-GBM disease. Methods: We performed the first genome-wide association study in 190 patients with anti-GBM disease and 194 ancestry matched control participants. We carried out imputation and conditional analyses to identify single-nucleotide polymorphisms associated with genetic susceptibility to the disease. The structures of HLA molecules interacting with pathogenic peptide were further conducted using AlphaFold 3. Results: We identified 2 loci significantly associated with disease risk. The strongest association was mapped to major histocompatibility complex region at rs9270596 of 6p21.32 near HLA-DRB1 (odds ratio OR = 8.93; P = 1.57 x 10-18). HLA fine-mapping further identified the dominant risk allele associated with the disease as HLA-DRB1*1501 (OR = 8.77; P = 2.86 x 10-18), where the alanine (Ala) residue at position 71 was associated with an increased risk (OR = 7.61; P = 4.15 x 10-17). An addition new risk allele was identified at rs7442445 of SHROOM3 on 4q21.1 (OR = 2.56; P = 3.45 x 10-6). Structure analyses revealed that HLA-DR15-α3135-145 binding was significantly attenuated due to alterations in physiochemical properties of risk-associated amino acids comprising epitope-binding pockets. Conclusion: Our findings revealed two genetic loci associated with anti-GBM disease, providing more detailed evidence for the role of genetic predisposition in the development of anti-GBM disease.