Epistasis between HLA-DRB1 parental alleles in a Spanish cohort with multiple sclerosis

Romero-Pinel, Lucía; Pujal, Josep María; Martínez-Yélamos, Sergio; Gubieras, L.; Matas, Elisabet; Bau, Laura; Torrabadella, M; Azqueta, Carmen; Arbizu, Txomin

doi:10.1016/j.jns.2010.07.026

Cited by 2 publications

(3 citation statements)

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“…Population studies have established the risk contribution of DQA and DQB HLA Class II alleles in concert with DRB1, and have also defined the DRB1*15 risk contribution as being fundamentally subject to its overall HLA haplotype and hence potentially epistasis . Epistasis between HLA alleles has been identified in several ethnic populations, further cementing the importance HLA‐region gene–gene interactions …”

Section: Epistasis In Multiple Sclerosismentioning

confidence: 99%

“…101 Epistasis between HLA alleles has been identified in several ethnic populations, further cementing the importance HLA-region gene-gene interactions. [102][103][104] It is firmly established that HLA alleles play a major role in MS, and although studying the role of HLA-mediated epistasis in MS is valuable in understanding the complexities of inherited risk, it is unlikely to yield new therapeutic targetsthe discovery of novel therapeutic targets in MS, and other complex diseases, will require the integration of genomic, transcriptional and functional research ( Fig. 1).…”

Section: Epistasis In Multiple Sclerosismentioning

confidence: 99%

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Epistasis and immunity: the role of genetic interactions in autoimmune diseases

Rose¹,

Bell

2012

Immunology

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SummaryAutoimmune disorders are a complex and varied group of diseases that are caused by breakdown of self-tolerance. The aetiology of autoimmunity is multi-factorial, with both environmental triggers and genetically determined risk factors. In recent years, it has been increasingly recognized that genetic risk factors do not act in isolation, but rather the combination of individual additive effects, gene-gene interactions and geneenvironment interactions determine overall risk of autoimmunity. The importance of gene-gene interactions, or epistasis, has been recently brought into focus, with research demonstrating that many autoimmune diseases, including rheumatic arthritis, autoimmune glomerulonephritis, systemic lupus erythematosus and multiple sclerosis, are influenced by epistatic interactions. This review sets out to examine the basic mechanisms of epistasis, how epistasis influences the immune system and the role of epistasis in two major autoimmune conditions, systemic lupus erythematosus and multiple sclerosis.Keywords: autoimmunity; epistasis; genetic interaction; multiple sclerosis; systemic lupus erythematosus.In the era of systems biology, it is no longer possible to consider a gene in isolation: it is increasingly apparent that we must consider the interactions of a gene, including the interactions of its protein product, gene-environment interactions and gene-gene interactions. This is particularly relevant in complex human disease, where aetiology is multi-factorial. Autoimmune diseases are a varied group of complex disorders, with a strong genetic component, caused by breakdown of self-tolerance. This review sets out to examine the role of gene-gene interactions in autoimmunity: we review the known mechanisms of epistasis, and suggest where in the immune system they might act. We proceed to draw on disease-specific examples from two complex autoimmune conditions: multiple sclerosis (MS) and systemic lupus erythematosus (SLE). Understanding epistasis: basic principlesThe term epistasis has been used for over 100 years, being first used by Bateson to describe the masking of one disease-causing mutation by the co-inheritance of a mutation at a separate locus. 1 The idea has since been expanded to include any statistical deviation from the additive combination of two loci, the definition that is most commonly used today. 2,3 At first, this might seem a complex mathematical concept, but this is not the case. In simple terms, epistasis is the phenomenon whereby the effect of one genetic variant is altered by another. The term can be used interchangeably with gene-gene interaction, or genetic interactions.It has been known for many years that disease-causing mutations show wide phenotypic variability, even within families, emphasizing that mutation outcome is dependent on the genetic background, as well as on environmental factors. There are many examples of simple Mendelian diseases showing phenotypic variability. An example in immunological disease comes from the study of X-linked lymphoproliferativ...

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Section: Epistasis In Multiple Sclerosismentioning

confidence: 99%

Section: Epistasis In Multiple Sclerosismentioning

confidence: 99%

Epistasis and immunity: the role of genetic interactions in autoimmune diseases

Rose¹,

Bell

2012

Immunology

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“…Several large recent studies have shown that the presence of DRB1*15:01 is positively associated with OCB (Leone et al 2013;Mero et al 2013;Romero-Pinel et al 2010) and that carriage of DRB1*15 together with the presence of OCB hastens the attainment of an EDSS of 6.0 (Imrell et al 2009). In contrast, genotypes containing DRB1*04:04 were found to increase the risk of being OCB negative.…”

Section: Hla Effects On Paraclinical Measures Of Msmentioning

confidence: 99%

The Role of HLA in MS Susceptibility and Phenotype

Greer

2014

Emerging and Evolving Topics in Multiple Sclerosis Pathogenesis and Treatments

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One of the most consistent findings in multiple sclerosis (MS) is that development of MS is linked with carriage of the class II human leucocyte antigen (HLA) molecule HLA-DRB1*15:01; around 60 % of Caucasian MS patients carry this allele compared to 25-30 % of ethnically matched healthy individuals. However, other HLA molecules have also been linked to the development of MS. In this chapter, the association between different HLA types and susceptibility to MS will be reviewed, and other linkages between the carriage of specific HLA molecules and clinical and experimental findings in MS will be considered.

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Epistasis between HLA-DRB1 parental alleles in a Spanish cohort with multiple sclerosis

Cited by 2 publications

References 36 publications

Epistasis and immunity: the role of genetic interactions in autoimmune diseases

Epistasis and immunity: the role of genetic interactions in autoimmune diseases

The Role of HLA in MS Susceptibility and Phenotype

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