Major Histocompatibility Complex: Disease Associations

Abstract

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

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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. http://www.els.net [doi: 10.1002/9780470015902.a0001286.pub3]