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

Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, Vyse TJ, Rioux JD - PLoS Genet. (2008)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Genetics and Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom.

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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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.
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pgen-1000024-g002: 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.

Mentions: Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each serological, mixed lymphocyte reaction, or molecular specificity (see Text S1). These data were collated (Table S2) and used to create Figures 1 and 2. The extended LD observed at the MHC does not allow differentiation between allelic and haplotypic association in the current pooled analysis. Thus, as it is vital to consider LD when interpreting association results at the MHC, our figures display statistically significant variants on the basis of “ancestral,” also known as “conserved extended,” haplotypes [10]–[12].


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

Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, Vyse TJ, Rioux JD - PLoS Genet. (2008)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2291482&req=5

pgen-1000024-g002: 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.
Mentions: Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each serological, mixed lymphocyte reaction, or molecular specificity (see Text S1). These data were collated (Table S2) and used to create Figures 1 and 2. The extended LD observed at the MHC does not allow differentiation between allelic and haplotypic association in the current pooled analysis. Thus, as it is vital to consider LD when interpreting association results at the MHC, our figures display statistically significant variants on the basis of “ancestral,” also known as “conserved extended,” haplotypes [10]–[12].

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Genetics and Rheumatology, Faculty of Medicine, Imperial College London, London, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus