Major Histocompatibility Complex: Disease Associations

Human major histocompatibility complex (MHC) alleles can be used as markers for a wide variety of autoimmune and other disorders. The interpretation of and possible bases for these associations can be considered in relation to conserved extended MHC haplotypes (CEHs). The latter are fixed stretches of up to several million base pairs of genomic deoxyribonucleic acid (DNA). CEHs constitute at least a third of normal European Caucasian MHC haplotypes and contribute most of the MHC disease susceptibility genetic markers. Whereas this has facilitated the detection of MHC gene-disease association, it paradoxically makes the identification of true susceptibility genetic loci (as distinguished from genetic markers) more difficult. It is likely that the great majority of true susceptibility genes for MHC-associated diseases are yet to be discovered. It may take new methods and new approaches to identify the true MHC susceptibility genes and their relation to many of the polygenic MHC-associated diseases.

Keywords: major histocompatibility complex (MHC); disease; haplotype; allele–disease association; Caucasian

 References
    Ahmed AR, Yunis EJ, Khatri K et al. (1990) Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris. Proceedings of the National Academy of Sciences of the USA 87: 7658–7662.
    Alper CA and Awdeh Z (2000) Incomplete penetrance of MHC susceptibility genes: prospective analysis of polygenic MHC-determined traits. Tissue Antigens 56: 199–206.
    Alper CA, Dubey DP, Yunis EJ and Awdeh Z (2000) A simple estimate of the general population frequency of the MHC susceptibility gene for autoimmune polygenic disease. Experimental and Clinical Immunogenetics 17: 138–147.
    Alper CA, Larsen CE, Dubey DP et al. (2006) The haplotype structure of the human major histocompatibility complex. Human Immunology 67: 73–84.
    Aly TA, Eller E, Ide A et al. (2006) Multi-SNP analysis of MHC region: remarkable conservation of HLA-A1-B8-DR3 haplotype. Diabetes 55: 1265–1269.
    Awdeh ZL, Yunis EJ, Audeh MJ et al. (2006) A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease. Journal of Autoimmunity 27: 174–181.
    Bilbao JR, Calvo B, Aransay AM et al. (2006) Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease. Genes and Immunity 7: 550–554.
    Cullen LM, Anderson GJ, Ramm GA, Jazwinska EC and Powell LW (1999) Genetics of hemochromatosis. Annals of Internal Medicine 50: 87–98.
    Feder JN, Gnirke A, Thomas W et al. (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics 13: 399–408.
    Fleischnick E, Awdeh ZL, Raum D et al. (1983) Extended MHC haplotypes in 21-hydroxylase deficiency congenital adrenal hyperplasia: shared genotypes in unrelated patients. Lancet 1: 152–156.
    Raum D, Awdeh Z, Yunis EJ, Alper CA and Gabbay KH (1984) Extended major histocompatibility complex haplotypes in type I diabetes mellitus. Journal of Clinical Investigation 74: 449–454.
    Simon M, Bourel M, Alexandre JL et al. (1976) HLA and ‘non-immunological’ disease: idiopathic haemochromatosis. Lancet 308: 973–974.
    Smith WP, Yu Q, Li SS et al. (2006) Toward understanding MHC disease associations: partial resequencing of 46 distinct HLA haplotypes. Genomics 87: 561–571.
    book Svejgaard A and Ryder LP (1977) "Associations between HLA and disease". In: Dausset LJ and Svejgaard A (eds) HLA and Disease, pp. 46–53. Copenhagen: Munksgaard.
    book Thomson G and Bodmer W (1977) "The genetic analysis of HLA and disease association". In: Dausset J and Svejgaard A (eds) HLA and Disease, pp. 84–93. Copenhagen: Munksgaard.
    White PC, New M and Dupont B (1984) HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for seroid 21-hydroxylation. Proceedings of the National Academy of Sciences of the USA 81: 7505–7509.
    Woolf B (1955) On estimating the relation between blood group and disease. Annals of Human Genetics 19: 251–253.
 Further Reading
    Cudworth AG and Woodrow JC (1975) Evidence for HL-A-linked genes in ‘juvenile’ diabetes mellitus. British Medical Journal 3: 133–135.
    Kruskall MS, Alper CA, Awdeh Z, Yunis EJ and Marcus-Bagley D (1992) The immune response to hepatitis B vaccine in humans: inheritance patterns in families. Journal of Experimental Medicine 175: 495–502.
    Larsen CE and Alper CA (2004) The genetics of HLA-associated disease. Current Opinion in Immunology 16: 660–667.
    Ott J (1974) Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. American Journal of Human Genetics 26: 588–597.
    Rubinstein P, Suciu-Foca N and Nicholson JF (1977) Genetics of juvenile diabetes mellitus. A recessive gene closely linked to HLA-D and with 50 per cent penetrance. New England Journal of Medicine 297: 1036–1040.
    Thomson G (1995) Analysis of complex human traits: an ordered notation method and new tests for mode of inheritance. Critical Reviews in Clinical Laboratory Sciences 32: 183–219.
    book Tiwari JL and Terasaki PI (1985) HLA and Disease Association. New York: Springer.
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Alper, Chester A(Mar 2009) Major Histocompatibility Complex: Disease Associations. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001286.pub2]