Fine-Scale Mapping atIGAD1and Genome-Wide Genetic Linkage Analysis ImplicateHLA-DQ/DRas a Major Susceptibility Locus in Selective IgA Deficiency and Common Variable Immunodeficiency

摘要: Selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID) are the most primary immunodeficiencies in humans. A high degree of familial clustering, marked differences population prevalence among ethnic groups, association IgAD CVID families, a predominant inheritance pattern multiple-case pedigrees have suggested strong, shared genetic predisposition. Previous linkage, case-control, family-based studies mapped an IgAD/CVID susceptibility locus, designated IGAD1, to MHC, but its precise location within MHC has been controversial. We analyzed sample 101 multiple- 110 single-case families using 36 markers at IGAD1 candidate region homozygous stretches across by affected family members. Haplotype analysis, linkage disequilibrium, homozygosity mapping indicated that HLA-DQ/DR is major strongly suggesting autoimmune pathogenesis IgAD/CVID. This supported highest excess allelic sharing 6p genome-wide analysis 383 marker loci, previously reported restrictions T cell repertoires CVID, presence autoantibodies, impaired activation, dysregulation number genes targeted immune system. may thus provide useful model for study novel therapeutic strategies diseases.