title: Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, -A1 haplotypes.
abstract: BACKGROUND
  A common genetic basis for IgA deficiency (IgAD) and common variable immunodeficiency (CVID) is suggested by their occurrence in members of the same family and the similarity of the underlying B cell differentiation defects. An association between IgAD/CVID and HLA alleles DR3, B8, and A1 has also been documented. In a search for the gene(s) in the major histocompatibility complex (MHC) that predispose to IgAD/CVID, we analyzed the extended MHC haplotypes present in a large family with 8 affected members.
  
  
  METHODS
  We examined the CVID proband, 72 immediate relatives, and 21 spouses, and determined their serum immunoglobulin concentrations. The MHC haplotype analysis of individual family members employed 21 allelic DNA and protein markers, including seven newly available microsatellite markers.
  
  
  RESULTS
  Forty-one (56%) of the 73 relatives by common descent were heterozygous and nine (12%) were homozygous for a fragment or the entire extended MHC haplotype designated haplotype 1 that included HLA- DR3, -C4A-0, -B8, and -A1. The remarkable prevalence of haplotype 1 was due in part to marital introduction into the family of 11 different copies of the haplotype, eight sharing 20 identical genotype markers between HLA-DR3 and HLA-B8, and three that contained fragments of haplotype 1.
  
  
  CONCLUSIONS
  Crossover events within the MHC indicated a susceptibility locus for IgAD/CVID between the class III markers D821/D823 and HLA-B8, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CVID in this family.
authors.affiliation: Department of Medicine, Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA. Harry.Schroeder@ccc.uab.edu
authors.forename: H W
authors.initials: HW
authors.lastname: Schroeder
authors.forename: Z B
authors.initials: ZB
authors.lastname: Zhu
authors.forename: R E
authors.initials: RE
authors.lastname: March
authors.forename: R D
authors.initials: RD
authors.lastname: Campbell
authors.forename: S M
authors.initials: SM
authors.lastname: Berney
authors.forename: S A
authors.initials: SA
authors.lastname: Nedospasov
authors.forename: R L
authors.initials: RL
authors.lastname: Turetskaya
authors.forename: T P
authors.initials: TP
authors.lastname: Atkinson
authors.forename: R C
authors.initials: RC
authors.lastname: Go
authors.forename: M D
authors.initials: MD
authors.lastname: Cooper
authors.forename: J E
authors.initials: JE
authors.lastname: Volanakis
mesh_terms: D000328:Adult; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D005819:Genetic Markers; D015788:HLA-A1 Antigen / Q000235:genetics*; D015795:HLA-B8 Antigen / Q000235:genetics*; D015803:HLA-DR3 Antigen / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D017098:IgA Deficiency / Q000235:genetics*; D007223:Infant; D008297:Male; D010375:Pedigree
chemical_list: D005819:Genetic Markers; D015788:HLA-A1 Antigen; D015795:HLA-B8 Antigen; D015803:HLA-DR3 Antigen