A putative susceptibility locus on chromosome 18 is not a major contributor to human selective IgA deficiency: evidence from meiotic mapping of 83 multiple-case families.
Previous reports of an association between constitutional chromosome 18 abnormalities and low levels of IgA suggested that this chromosome contains a susceptibility locus for selective IgA deficiency (IgAD), the most frequent Ig deficiency in humans. IgAD is genetically related to common variable immunodeficiency (CVID), characterized by a lack of additional isotypes. Our previous linkage analysis of 83 multiple-case IgAD/CVID families containing 449 informative pedigree members showed a significantly increased allele sharing in the chromosome region 6p21 consistent with allelic associations in family-based and case-control studies and provided the evidence for a predisposing locus, termed IGAD1, in the proximal part of the MHC. We have typed the same family material at 17 chromosome 18 marker loci with the average intermarker distance of 7 cM. A total of 7633 genotypes were analyzed in a nonparametric linkage analysis, but none of the marker loci exhibited a significantly increased allele sharing in affected family members. In addition, reverse painting and deletion mapping of a panel of constitutional chromosome 18 deletions/translocations showed the presence of IgA-deficient and IgA-proficient patients with the same abnormality and did not reveal a region commonly deleted. The linkage analysis of chromosome 8 and 21 regions involved in reciprocal translocations t(8;18) and t(18;21), which were identified in two patients lacking IgA, did not disclose a significant allele sharing. Although these results do not exclude the presence of a minor predisposing locus on this chromosome, such a putative locus would confer a population risk of developing IgAD/CVID much lower than IGAD1.
Vorechovský
I
I
Karolinska Institute at NOVUM, Center for Biotechnology, Huddinge, Sweden. igor.vorechovsky@cbt.ki.se
Blennow
E
E
Nordenskjöld
M
M
Webster
A D
AD
Hammarström
L
L
D016022:Case-Control Studies; D002869:Chromosome Aberrations / Q000097:blood / Q000235:genetics / Q000276:immunology; D025063:Chromosome Disorders; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics* / Q000276:immunology; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage / Q000276:immunology; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000276:immunology*; D006801:Humans; D017098:IgA Deficiency / Q000097:blood / Q000235:genetics*; D007070:Immunoglobulin A / Q000097:blood; D008297:Male; D008540:Meiosis / Q000235:genetics* / Q000276:immunology; D014178:Translocation, Genetic / Q000276:immunology
D005819:Genetic Markers; D007070:Immunoglobulin A