Since the complete sequencing of a human major histocompatibility complex (MHC) haplotype, interest in non-human leucocyte antigen (HLA) genes encoded in the MHC has been growing. Non-HLA genes, which outnumber the HLA genes, may contribute to or account for HLA and disease associations. Most information on non-HLA genes has been obtained in separate studies of individual loci. To comprehensively address polymorphisms of relevant non-HLA genes in ‘conserved extended haplotypes’ (CEH), we investigated 101 International Histocompatibility Workshop reference cell lines and nine additional anonymous samples representing all 37 unambiguously characterized CEHs at MICA, NFKBIL1, LTA, NCR3, AIF1, HSPA1A, HSPA1B, BF, NOTCH4 and a single nucleotide polymorphism (SNP) at HLA-DQA1 as well as MICA, NOTCH4, HSPA1B and all five tumour necrosis factor short tandem repeat (STR) polymorphisms. This work (1) provides an extensive catalogue of MHC polymorphisms in all CEHs, (2) unravels interrelationships between HLA and non-HLA haplotypical lineages, (3) resolves reported typing ambiguities and (4) describes haplospecific markers for a number of CEHs. Analysis also identified a DQA1 SNP and segments containing MHC class III polymorphisms that corresponded with class II (DRB3 and DRB4) lineages. These results portray the MHC where lineages containing non-HLA and HLA variants in linkage disequilibrium may operate in concert and can guide more thorough design and interpretation of HLA–disease relationships.
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This study was partially funded by intramural funds from the University of Alabama at Birmingham School of Public Health. We thank the staff at the Tissue Typing Laboratory in Glasgow Royal Infirmary (Scotland, UK), the Regional Tissue Typing Laboratory in the Welsh Blood Service (UK) and the HLA Laboratory in Martin Luther University School of Medicine at Halle (Germany) for various contributions to this study. M Tevfik Dorak is currently supported by the North of England Children's Cancer Research Fund.
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Dorak, M., Shao, W., Machulla, H. et al. Conserved extended haplotypes of the major histocompatibility complex: further characterization. Genes Immun 7, 450–467 (2006). https://doi.org/10.1038/sj.gene.6364315
- major histocompatibility complex
- human leukocyte antigens
- genetic variation or genetic polymorphism
- genetic predisposition to disease
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