Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition.
Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of terminal lymphocyte differentiation, leading to a lack of IgA in serum and mucosal secretions. Familial clustering, variable population prevalence in different ethnic groups, and a predominant inheritance pattern suggest a strong genetic predisposition to IgAD. The genetic susceptibility to IgAD is shared with a less prevalent, but more profound, defect called "common variable immunodeficiency" (CVID). Here we show an increased allele sharing at 6p21 in affected members of 83 multiplex IgAD/CVID pedigrees and demonstrate, using transmission/diseqilibrium tests, family-based associations indicating the presence of a predisposing locus, designated "IGAD1," in the proximal part of the major histocompatibility complex (MHC). The recurrence risk of IgAD was found to depend on the sex of parents transmitting the defect: affected mothers were more likely to produce offspring with IgAD than were affected fathers. Carrier mothers but not carrier fathers transmitted IGAD1 alleles more frequently to the affected offspring than would be expected under random segregation. The differential parent-of-origin penetrance is proposed to reflect a maternal effect mediated by the production of anti-IgA antibodies tentatively linked to IGAD1. This is supported by higher frequency of anti-IgA-positive females transmitting the disorder to children, in comparison with female IgAD nontransmitters, and by linkage data in the former group. Such pathogenic mechanisms may be shared by other MHC-linked complex traits associated with the production of specific autoantibodies, parental effects, and a particular MHC haplotype.
Vorechovský
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I
Karolinska Institute, Department of Biosciences at NOVUM, Huddinge, Sweden. igor.vorechovsky@cbt.ki.se
Webster
A D
AD
Plebani
A
A
Hammarström
L
L
D000483:Alleles; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000276:immunology; D020090:Chromosome Segregation / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D017098:IgA Deficiency / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D007070:Immunoglobulin A / Q000097:blood / Q000235:genetics / Q000276:immunology; D015810:Linkage Disequilibrium / Q000235:genetics; D008285:Major Histocompatibility Complex; D008297:Male; D010290:Parents; D019683:Penetrance; D012727:Sex Characteristics
D000888:Antibodies, Anti-Idiotypic; D007070:Immunoglobulin A