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 should 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. While 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.

Key Concepts

  • Most human major histocompatibility complex (MHC)‐associated diseases and physiological disorders are complex conditions whose genetic architecture remains largely unknown.
  • The genetic architecture of simple Mendelian MHC‐associated conditions help us understand the bases for MHC associations in more complex conditions.
  • The genomic architecture of the MHC, strongly influenced by the presence of conserved extended haplotypes (CEHs), which are 1–5 megabase essentially identical by descent common population MHC haplotypes, should be considered when analysing MHC disease markers.
  • Association studies that dissect disease genetic architecture (including MHC‐linked mode of inheritance) provide far greater biological insight than ‘risk’‐based statistical associations.
  • Family‐based association studies provide far better insight into MHC‐linked diseases and are less affected by population stratification than case versus control association studies.
  • Significant deviation from random affected sib pair allele/haplotype sharing is required to confirm the biological relevance of detected MHC associations.
  • Hypotheses based on the statistical association of particular single nucleotide polymorphisms or particular amino acids in candidate disease genes are moot until biological evidence is provided that such candidate genes play a causal role in such diseases.
  • The era of ‘personalised’ or ‘precision’ genetics will require both family‐based and directly observed data and should not rely on statistically associated and/or imputed results.

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


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 United States of America 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 (2000a) 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 , Marcus‐Bagley D , Awdeh Z , et al. (2000b) Prospective analysis suggests susceptibility genes for deficiencies of IgA and several other immunoglobulins on the [HLA‐B8, SC01, DR3] conserved extended haplotype. Tissue Antigens 56: 207–216.

Alper CA , Xu J , Cosmopoulos K , et al. (2003) Immunoglobulin deficiencies and susceptibility to infection among homozygotes and heterozygotes for C2 deficiency. Journal of Clinical Immunology 23: 297–305.

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 , Raum D , Yunis EJ and Alper CA (1983) Extended HLA/complement allele haplotypes: evidence for T/t‐like complex in man. Proceedings of the National Academy of Sciences of the United States of America 80: 259–263.

Awdeh ZL and Alper CA (2005) Mendelian inheritance of polygenic diseases: a hypothetical basis for increasing incidence. Medical Hypotheses 64: 495–498.

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.

Calvo B , Castano L , Marcus‐Bagley D , et al. (2000) The [HLA‐B18, F1C30, DR3] conserved extended haplotype carries a susceptibility gene for IgD deficiency. Journal of Clinical Immunology 20: 216–220.

Cullen LM , Anderson GJ , Ramm GA , Jazwinska EC and Powell LW (1999) Genetics of hemochromatosis. Annals of Internal Medicine 50: 87–98.

Falk CT and Rubinstein P (1987) Haplotype relative risks: an easy way to construct a proper control sample for risk calculations. Annals of Human Genetics 51: 227–233.

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.

Hyttinen V , Kaprio J , Kinnunen L , Koskenvuo M and Tuomilehto J (2003) Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs. Diabetes 52: 1052–1055.

Jia X , Han B , Onengut‐Gumuscu S , et al. (2013) Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 8 (6): e64683.

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.

Larsen CE , Alford DR , Trautwein MR , et al. (2014) Dominant sequences of human major histocompatibility complex conserved extended haplotypes from HLA‐DQA2 to DAXX. PLoS Genetics 10 (10): e1004637.

Raum D , Awdeh Z and Alper CA (1981) BF types and the mode of inheritance of insulin‐dependent diabetes mellitus (IDDM). Immunogenetics 12: 59–74.

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.

Rjasanowski I , Költing I and Kerner W (2003) Frequency of diabetes transmission from two type 1 diabetic parents to their children. Diabetes Care 26: 2219–2220.

Rubinstein P , Walker M , Carpenter C , et al. (1981) The use of the haplotype relative risk (HRR) and the “haplo‐delta” (Dh) estimates in juvenile diabetes from three racial groups. Human Immunology 3: 384.

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.

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.

Szilágyi A , Bánlaki Z , Pozsonyi E , et al. (2010) Frequent occurrence of conserved extended haplotypes (CEHs) in two Caucasian populations. Molecular Immunology 47: 1899–904.

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.

Thomson G (1988) HLA disease associations: models for insulin dependent diabetes mellitus and the study of complex human genetic disorders. Annual Review of Genetics 22: 31–50.

Wang C , Krishnakumar S , Wilhelmy J , et al. (2012) High‐throughput, high‐fidelity HLA genotyping with deep sequencing. Proceedings of the National Academy of Sciences of the United States of America 109: 8676–8681.

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 steroid 21‐hydroxylation. Proceedings of the National Academy of Sciences of the United States of America 81: 7505–7509.

Woolf B (1955) On estimating the relation between blood group and disease. Annals of Human Genetics 19: 251–253.

Yunis EJ , Larsen CE , Fernandez‐Viña M , et al. (2003) Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks. Tissue Antigens 62: 1–20.

Further Reading

Cudworth AG and Woodrow JC (1975) Evidence for HL‐A‐linked genes in ‘juvenile’ diabetes mellitus. British Medical Journal 3: 133–135.

Fraga MF , Ballestar E , Paz MF , et al. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences of the United States of America 102: 10604–9.

Glusman G , Cox HC and Roach JC (2014) Whole‐genome haplotyping approaches and genomic medicine. Genome Medicine 6 (9): 73.

Madsen AM , Hodge SE and Ottman R (2011) Causal models for investigating complex disease: I. A primer. Human Heredity 72: 54–62.

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.

Raffel LJ , Goodarzi MO and Rotter JI (2007) Diabetes mellitus. In: Rimoin DL , Connor JM , Pyeritz RE and Korf BR (eds) Emery and Rimoin's Principles and Practice of Medical Genetics, 5th edn, volume 2, chap. 90, pp. 1980–2022. Philadelphia: Churchill‐Livingstone Elsevier.

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.

Tiwari JL and Terasaki PI (1985) HLA and Disease Association. New York: Springer.

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Alper, Chester A, and Larsen, Charles E(Jul 2015) Major Histocompatibility Complex: Disease Associations. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001286.pub3]