Impact of linkage disequilibrium on studies of the HLA complex

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Regardless of the basis for linkage disequilibrium, it has an important impact upon analyses of HLA antigens in functional and disease association studies. A historical review of the HLA antigens found to be associated with certain diseases illustrates this point. As new loci within the HLA complex were identified, associations with allelic variants of these new loci in linkage disequilibrium were shown to be stronger than previously observed associations. The number of genes mapping to the HLA complex continues to increase. Due to linkage disequilibrium, functional associations with allelic variants of the newly defined loci may be stronger than those observed with previously characterized loci.

While the HLA gene complex provides the best known examples of linkage disequilibrium, this phenomenon is not limited to HLA. Linkage disequilibrium may also be a consideration when examining other gene complexes encoding immunologically relevant molecules. For example, the immunoglobulin heavy chain and T cell receptor and gene complexes are composed of linked gene segments that show allelic variations. Allotype markers (Gm) for the constant region of immunoglobulin G (IgG) heavy chain are inherited as fixed combinations or haplotypes that have been used as markers for various populations. The stability of Gm haplotypes suggests that linkage disequilibrium may be operative. In contrast, available information on the T cell receptor a and (3 chain gene complexes suggest that linkage disequilibrium is not a major determinant. Considering the relative physical sizes of T cell receptor a and (3 gene complexes, there is extensive heterogeneity observed in the combination of markers present in haplotypes, suggesting that recombination has occurred frequently within the T cell receptor gene complexes.

See also: Allotypes, immunoglobin; H2 class I; H2 class II; H2 class III; HLA class I; HLA class II; HLA class III region; Immunoglobulin genes; Immunoglobulin structure; MHC disease associations; Relative risk; T cell receptor, aß.

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