IgA vasculitis sibling clustering: From HLA-DRB1 genetic burden to nephritis risk stratification

IgA vasculitis (IgAV) is the most common systemic small-vessel vasculitis in childhood, with an annual incidence of 3 to 26.7 per 100,000 children. Although it is predominantly sporadic, its 1.9% familial clustering rate and significant tendency for sibling comorbidity suggest a non-random pathogenesis. Multicohort GWAS data confirm that HLA-DRB1*01 and HLA-DRB1*11 are common genetic risk loci across ethnic groups. Furthermore, the core pathogenic molecule, galactose-deficient IgA1 (Gd-IgA1), exhibits a heritability of up to 64% in affected families, constituting the intrinsic basis for sibling concordance. Regarding the triggering mechanism, approximately 75% of IgAV cases are preceded by upper respiratory or gastrointestinal prodromal infections; the cross-transmission of streptococci and viruses within the family environment provides the external trigger for sibling-to-sibling transmission. Clinical phenotypes show that familial cases exhibit high consistency in the pattern of target organ involvement, and the renal involvement in the index case has significant predictive value for stratifying sibling risk. This article proposes potential mechanisms underlying the synchronized onset of disease and the formation of phenotypic mirroring among siblings, aiming to establish a clinical system for early warning and precise intervention based on family history.