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Fine-Scale Mapping at IGAD1 and Genome-Wide Genetic Linkage Analysis Implicate HLA-DQ/DR as a Major Susceptibility Locus in Selective IgA Deficiency and Common Variable Immunodeficiency ¹

Jana Kralovicova^*, Lennart Hammarström, Alessandro Plebani, A. David B. Webster and Igor Vorechovsky^2,*

^* Division of Human Genetics, School of Medicine, Southampton University Hospital, University of Southampton, Southampton, United Kingdom; Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden; Istituto di Medicina Molecolare Angelo Nocivelli, University of Brescia, Brescia, Italy; Royal Free Campus, University College London, London, United Kingdom

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

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