Patients with IgA deficiency may have severe anaphylactic reactions to transfused blood and increased susceptibility to infections. It is known that 4 conserved extended major histocompatibility haplotypes are increased in frequency among IgA-deficient patients. This project will further define the genetics of IgA deficiency and a group of closely related and more common deficiencies of IgD, of IgG3 and of IgG4 by first identifying susceptibility and non-susceptibility conserved extended haplotypes. We will use known sequences and polymorphisms (microsatellites, SNPs, etc.) to preliminarily localize susceptibility genes for each of the immunoglobulin deficiencies by prospective study of individuals with ancient recombinant haplotypes or fragments of extended haplotypes who have immunoglobulin deficiencies. Nucleotide sequences in chromosomal regions identified in these studies will be determined in susceptibility and non-susceptibility extended haplotypes in order to identify candidate susceptibility genes as open reading frames. Polymorphisms will be corrected with those of patients with deficiencies but without extended haplotypes. Expression of genes in the region will be assessed in cells of the peripheral blood mononuclear cells of deficient and normal persons, including affected B cell subsets and their immediate progenitors and, if differences are found, these will be correlated with the presence of deficiency. From the study of appropriate family members who have immunoglobulin deficiencies and using analytic tools that we have developed, we shall construct a general genetic and population genetic model for IgA deficiency and each of the other MHC-determined immunoglobulin deficiencies and estimate MHC and non-MHC gene frequencies and confirm modes of inheritance. We will determine prevalences of deficiencies in their sibs, MHC-identical sibs , parents and clildren and compare these with those predicted by the model to validate the model.
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