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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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Related in: MedlinePlus

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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pgen-1000024-g003: 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.

Mentions: The pooled analysis highlights a number of commonalities as well as differences across the six diseases (Figure 3). The most frequently shared disease susceptibility alleles arise from HLA-DR4 haplotypes, which are observed in all cases except UC. HLA-DR3 haplotypes are clearly important in disease predisposition for SLE, MS, and T1D, while DR9 haplotypes are seen in T1D and RA. CD, UC, and RA share DR1 haplotypes, although the specific DR1 alleles differ, as is the case in SLE, MS, and UC, where different DR2 haplotypes are observed. The various TNF polymorphisms that show disease predisposition in RA, CD, MS, and SLE demonstrate an interesting paradox, as therapeutic TNF-alpha blockade for CD and RA is associated with the development of demyelination and antinuclear antibodies. The susceptibility alleles/haplotypes identified in this review therefore suggest both common and disease-specific pathogenetic mechanisms in autoimmunity.


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000024-g003: 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.
Mentions: The pooled analysis highlights a number of commonalities as well as differences across the six diseases (Figure 3). The most frequently shared disease susceptibility alleles arise from HLA-DR4 haplotypes, which are observed in all cases except UC. HLA-DR3 haplotypes are clearly important in disease predisposition for SLE, MS, and T1D, while DR9 haplotypes are seen in T1D and RA. CD, UC, and RA share DR1 haplotypes, although the specific DR1 alleles differ, as is the case in SLE, MS, and UC, where different DR2 haplotypes are observed. The various TNF polymorphisms that show disease predisposition in RA, CD, MS, and SLE demonstrate an interesting paradox, as therapeutic TNF-alpha blockade for CD and RA is associated with the development of demyelination and antinuclear antibodies. The susceptibility alleles/haplotypes identified in this review therefore suggest both common and disease-specific pathogenetic mechanisms in autoimmunity.

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