PubMed · 2751821
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N Holmes. 1989. New HLA class I molecules.. https://doi.org/10.1016/0167-5699(89)90305-8
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Haplotypes are a powerful tool for identifying the genetic basis of common complex diseases. Disease-association mapping requires molecular methods for haplotyping biallelic SNP variation and highly complex polymorphisms. We developed a method for phasing HLA-A, HLA-B, and HLA-DRB1 alleles on chromosome 6 in unrelated individuals. This method uses the highly polymorphic HLA-B locus to discriminate the two HLA haplotypes in heterozygous individuals and its ideal location 1.4 Mbp telomeric to HLA-DRB1 and 1.2 Mbp centromeric to HLA-A to capture 2-Mbp-long genomic DNA. Genomic DNA representing a single HLA-B-captured haplotype is genotyped for HLA-A and HLA-DRB1 alleles and linkage to HLA-B is established. Proof of principle was established in a large blinded study of phase-known samples. Availability of an efficient method for MHC haplotype phase determination will facilitate the mapping of causative MHC-resident genes in many human diseases and has the potential to be broadened to other polymorphic gene complexes.
The HLA complex plays a prominent role in predisposition to many autoimmune diseases. Thus far, the highly polymorphic class I and class II loci have been considered as the prime candidates to explain this role. There is nonetheless growing evidence that other closely linked HLA loci are also involved in autoimmune susceptibility. Their search, however, has been hampered by the often strong linkage disequilibria, i.e. the non-random association of alleles at linked loci, across the HLA complex. Here, we discuss recent work from our laboratory on the dissection of this emblematic genetic region in a model autoimmune disease, acquired myasthenia gravis (MG).
Combinations of HLA and killer cell immunoglobulin-like receptor (KIR) genes have been associated with diseases as diverse as autoimmunity, viral infections, reproductive failure, and now cancer. Much as early observations of disease associations with HLA polymorphism preceded a detailed knowledge of HLA recognition by T cell receptors, the recently reported disease associations with HLA-KIR gene combinations beg for a better understanding of the underlying mechanisms.