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The complexity and diversity of major histocompatibility complex challenge disease association studies

Marja-Liisa Lokki1, Riitta Paakkanen1,2

  • 1Transplantation Laboratory, Department of Pathology, University of Helsinki, Helsinki, Finland.

HLA
|November 24, 2018
PubMed

Insights

The major histocompatibility complex (MHC) genes exhibit significant structural and functional variations, influencing immune-mediated diseases. Understanding MHC haplotypes is crucial for unraveling complex disease mechanisms beyond traditional immunology.

Area of Science:

  • Genetics
  • Immunology
  • Genomics

Background:

  • The human genome's Major Histocompatibility Complex (MHC) at 6p21.3 is characterized by high gene polymorphism, density, and functional cluster diversity.
  • MHC genes form haplotypes, exhibiting population-specific variations in linkage disequilibrium and regulatory interactions.
  • Expression quantitative trait loci studies have enhanced understanding of regulatory networks among MHC genes.

Purpose of the Study:

  • To elucidate the structural and functional variations within MHC genes and haplotypes.
  • To explore the role of MHC variations in selected immune-mediated diseases.
  • To provide a reference for future research on immune disorders and potential non-immunologic disease associations.

Main Methods:

  • Analysis of detailed MHC haplotype data.
  • Review of existing literature on gene expression quantitative trait loci (eQTLs).
  • Integration of immunological and genome-wide association study (GWAS) findings.

Main Results:

  • MHC haplotypes display considerable variation in strength and extent across different populations.
  • Cis- and trans-eQTLs reveal complex regulatory interactions between multiple MHC genes.
  • While numerous common variants influence complex diseases, individual effects are often small, necessitating comprehensive genomic and immunological approaches.

Conclusions:

  • MHC gene and haplotype variations are integral to understanding immune-mediated diseases.
  • Detailed MHC haplotype data serve as a valuable resource for future research, potentially identifying novel disease associations.
  • A holistic approach combining immunological assays and genomic analysis is essential for a complete understanding of complex disease mechanisms, as MHC alone is insufficient to predict susceptibility.

Keywords:
HLAMHCassociationdiseasehaplotypepopulations

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