A meta-analysis of interaction between Epstein-Barr virus and HLA-DRB1*1501 on risk of multiple sclerosis

Xiao, Di; Ye, Xingguang; Zhang, Na; Ou, Minglin; Guo, Congcong; Zhang, Baohuan; Liu, Yang; Wang, Man; Yang, Guang; Jing, Chunxia

doi:10.1038/srep18083

Cited by 52 publications

(29 citation statements)

References 51 publications

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“…These findings support a causal role for EBV in MS, modulated by HLA‐Class 1 genotype through alterations in antigen presentation to T cells. An additive interaction of EBV status with DRB1 has also been reported to modulate MS risk in Whites and Blacks …”

Section: Cause Versus Course – Are the Risk Factors Different?supporting

confidence: 66%

Environmental and genetic risk factors for MS: an integrated review

Waubant

Lucas

Mowry

et al. 2019

Ann Clin Transl Neurol

233

184

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Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.

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Section: Cause Versus Course – Are the Risk Factors Different?supporting

confidence: 66%

Environmental and genetic risk factors for MS: an integrated review

Waubant

Lucas

Mowry

et al. 2019

Ann Clin Transl Neurol

233

184

View full text Add to dashboard Cite

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“…Interactions have been demonstrated between several lifestyle and environmental risk factors for MS and presence of the strongest genetic risk factor, the HLA-DRB1*15:01 allele [5][6][7][8]. A synergistic effect between vitamin D and DRB1*15:01 has been suggested [9], whereas we found no such interaction in a previous study comprising a relatively small case-control sample [10].…”

Section: Introductioncontrasting

confidence: 83%

Low sun exposure increases multiple sclerosis risk both directly and indirectly

et al. 2019

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Objective We aimed to study (1) to what extent the influence of low sun exposure on multiple sclerosis (MS) risk is mediated by low vitamin D levels; (2) whether low sun exposure or vitamin D deficiency act synergistically with HLA-DRB1*15:01 and absence of HLA-A*02:01. Methods We used two population-based case-control studies (7069 cases, 6632 matched controls). Subjects with different HLA alleles, sun exposure habits and vitamin D status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Mediation analysis was used to identify the potential mediation effect of vitamin D on the relationship between low sun exposure and MS risk. Results Low sun exposure increased MS risk directly as well as indirectly, by affecting vitamin D status. The direct effect, expressed as OR, was 1.26 (95% CI 1.04-1.45) and the indirect effect, mediated by vitamin D deficiency, was 1.10 (95% CI 1.02-1.23). Of the total effect, nearly 30% was mediated by vitamin D deficiency. There was a significant interaction between low sun exposure and vitamin D deficiency (attributable proportion due to interaction 0.3, 95% CI 0.04-0.5) accounting for about 12% of the total effect. Further, both factors interacted with HLA-DRB1*15:01 to increase MS risk. Interpretation Our findings indicate that low sun exposure acts both directly on MS risk as well as indirectly, by leading to low vitamin D levels. The protective effect of sun exposure thus seems to involve both vitamin D and non-vitamin D pathways, which is of relevance for prevention, in particular for those with a genetic susceptibility to MS.

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“…7,29 T cells restricted to the HLADRB1*15 allele and linked to MS-related antigens seem to cross-react with the immunological response induced by the EBNA-1 sequence. 30 However, the latest meta-analysis revealed an additive but not synergistic effect between the two risk factors, corroborating that HLADRB1*15 carriage is not a confounding factor for EBV and MS. 31,32 A highly synergistic increase (14-fold) in MS risk was reported for EBV detection or IM combined with obesity, notably during adolescence. 7 However, there are conflicting results on the interaction between EBV and other well-established MS risk factors (reviewed also in 33 ).…”

Section: Epstein-barr Virus (Ebv)mentioning

confidence: 98%

Viruses and endogenous retroviruses in multiple sclerosis: From correlation to causation

et al. 2017

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Multiple sclerosis is an immune-mediated disease with an environmental component. According to a long-standing but unproven hypothesis dating to initial descriptions of multiple sclerosis (MS) at the end of the 19th century, viruses are either directly or indirectly implicated in MS pathogenesis. Whether viruses in MS are principally causal or simply contributory remains to be proven, but many viruses or viral elements-predominantly Epstein-Barr virus, human endogenous retroviruses (HERVs) and human herpesvirus 6 (HHV-6) but also less common viruses such as Saffold and measles viruses-are associated with MS. Here, we present an up-to-date and comprehensive review of the main candidate viruses implicated in MS pathogenesis and summarize how these viruses might cause or lead to the hallmark demyelinating and inflammatory lesions of MS. We review data from epidemiological, animal and in vitro studies and in doing so offer a transdisciplinary approach to the topic. We argue that it is crucially important not to interpret "absence of evidence" as "evidence of absence" and that future studies need to focus on distinguishing correlative from causative associations. Progress in the MS-virus field is expected to arise from an increasing body of knowledge on the interplay between viruses and HERVs in MS. Such interactions suggest common HERV-mediated pathways downstream of viral infection that cause both neuroinflammation and neurodegeneration. We also comment on the limitations of existing studies and provide future research directions for the field.

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A meta-analysis of interaction between Epstein-Barr virus and HLA-DRB1*1501 on risk of multiple sclerosis

Cited by 52 publications

References 51 publications

Environmental and genetic risk factors for MS: an integrated review

Environmental and genetic risk factors for MS: an integrated review

Low sun exposure increases multiple sclerosis risk both directly and indirectly

Viruses and endogenous retroviruses in multiple sclerosis: From correlation to causation

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