Defining the role of the MHC in autoimmunity: a review and pooled analysis - PubMed (original) (raw)

Review

Defining the role of the MHC in autoimmunity: a review and pooled analysis

Michelle M A Fernando et al. PLoS Genet. 2008.

Abstract

The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. MHC susceptibility alleles identified by pooled analysis: Multiple sclerosis, type 1 diabetes, and systemic lupus erythematosus.

Susceptibility is defined as a lower CI greater than 1.0. Shown are odds ratios with 95% CIs for MS (upper graph), T1D (middle graph), and SLE (lower graph). Beneath is a schematic representation of MHC class I, class III, and class II genes in genomic order but not to scale. Diamond size represents total number of cases included in pooled analysis for each allele. Diamond color reflects different disease-relevant ancestral haplotypes.

Figure 2

Figure 2. MHC susceptibility alleles identified by pooled analysis: Crohn's disease, ulcerative colitis, and rheumatoid arthritis.

Susceptibility is defined as a lower CI greater than 1.0. Shown are odds ratios with 95% CIs for CD (upper graph), UC (middle graph), and RA (lower graph). Beneath is a schematic representation of MHC class I, class III, and class II genes in genomic order but not to scale. Diamond size represents total number of cases included in pooled analysis for each allele. Diamond color reflects different disease-relevant ancestral haplotypes except for the shared epitope alleles in RA.

Figure 3

Figure 3. Illustration of the principal shared and distinct MHC haplotype associations in six immune-mediated diseases demonstrated by this pooled analysis.

This Venn diagram illustrates the principal shared and distinct MHC haplotype associations in MS, T1D, SLE, US, CD, and RA demonstrated by this pooled analysis. SLE is displayed at the centre of the figure, because it is a multisystem autoimmune disease, while the surrounding diseases are predominantly, though not exclusively, organ-specific. The HLA-DR variants indicated in the figure represent their respective extended haplotypes; TNF-alpha polymorphisms signify association at this gene alone.

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