<i>HLA-DRB1</i>
            and month of birth in multiple sclerosis

Ramagopalan, S V; Link, Jenny; Byrnes, Jake; Dyment, D A; Giovannoni, Gavin; Hintzen, Rogier Q.; Sundqvist, Emilie; Kockum, Ingrid; Smestad, C.; Lie, Benedicte A.; Harbo, Hanne F.; Padyukov, Leonid; Alfredsson, Lars; Olsson, Tomas; Sadovnick, A. Dessa; Hillert, J.; Ebers, George C.

doi:10.1212/wnl.0b013e3181c679f3

Cited by 49 publications

(48 citation statements)

References 26 publications

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“…It may be that the relatively long-lasting protection from MS acquired before adolescence by sun exposure or vitamin D status corresponds to a critical step of maturation of the thymus and the immune system [Tulic et al 2012], which could be favourably influenced by these environmental factors during the first part of life. To be more precise about this hypothetical mechanism, it has been suggested that vitamin D insufficiency in utero and during childhood may affect expression of HLA-DRB1 in the thymus, allowing autoreactive T cells to escape thymic deletion [Ramagopalan et al 2009a]. …”

Section: Genetic Risk Factors For Multiple Sclerosis Possibly Involvimentioning

confidence: 99%

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Pierrot‐Deseilligny

Souberbielle

2013

Ther Adv Neurol Disord

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Abstract:The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein-Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother's pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin.

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Section: Genetic Risk Factors For Multiple Sclerosis Possibly Involvimentioning

confidence: 99%

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Pierrot‐Deseilligny

Souberbielle

2013

Ther Adv Neurol Disord

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“…There are now 5 discrete insights relevant to this interaction which include the maternal parent-oforigin effects, 21 month of birth effects, 22 presence of vitamin D responsiveness in a susceptibility gene, 23 and transgenerational differences in allele frequency. 20 Here, we add a fifth interaction with gender ratio.…”

Section: Hla-drb1mentioning

confidence: 99%

MHC transmission

Chao¹,

Ramagopalan²,

Herrera³

et al. 2011

Neurology

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Objective: Major histocompatibility complex (MHC) genes dominate genetic susceptibility factors in multiple sclerosis (MS). Given the general consensus that incidence and prevalence of MS has been rising and specifically in women, we evaluated MHC-gender interactions. Methods:In a large family-based cohort consisting of 7,093 individuals (2,127 affected individuals) from 1,055 MS families, we examined MHC transmission by family structure and gender stratified by genetic distance of affected relatives from the MS proband. Conclusions: These observations implicate the MHC as the site of interactions and modifications mediating the female-to-male gender ratio in MS and its progressive increase. They further suggest this occurs via gene-environment interactions and epigenetic modifications in this region. ResultsThe difference between collateral and nuclear families provides some insight into the inheritance, decay, and gender specificity of putative epigenetic marks. Neurology The etiology of multiple sclerosis (MS) remains unclear; however, several lines of evidence suggest that MS is an acquired autoimmune disease and is triggered by environmental factors in genetically susceptible individuals. 1The main genetic contribution in MS comes from the major histocompatibility complex (MHC), and more specifically the human leukocyte antigen (HLA) Class II genes.2,3 Additional epistatic interactions and suppressor effects have also been observed within this locus. 4,5 There is general consensus that the incidence and prevalence of MS has been rising with an increased penetrance among women, 6 and excess monozygotic (MZ) twins concordance for MS is almost entirely female specific.7 Moreover, there is a maternal parent-of-origin effect 8 with higher number of affected mother-daughter pairs and few father-son pairs. 9There is little known about how the MHC might interact with the observed gender bias in MS. Since HLA alleles carry the strongest genetic susceptibility factors, we reasoned that the reported gender predisposition could be MHC-mediated. 10 Here we have used a large familye-Pub ahead of print on January 5, 2011, at www.neurology.org.

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“…40 This finding is in line with the hypothesis that vitamin D plays a critical role in nervous system development, 41 potentially modulating subsequent risk for neurological conditions like MS 42 and schizophrenia. 43 Their finding is further substantiated by a study that showed that the month of birth effect was only present among those with the risk allele, HLA-DRB1*15 44 , which is shown to interact with vitamin D due to the vitamin D-response element in its promoter. 20 Recent work suggests that deviations in the month of birth between samples and the general population are due to confounding and that these deviations are merely due to chance.…”

Section: Challenging Issues In Ms Epidemiological Researchmentioning

confidence: 91%

“…20 Recent work suggests that deviations in the month of birth between samples and the general population are due to confounding and that these deviations are merely due to chance. 45 While this may be a potential explanation, the study by Staples et al 40 that found the month-of-birth effect to be abrogated on adjustment for maternal sun exposure during pregnancy, and the Ramagopalan et al 44 study that found the association only present among those with the particular HLA-DRB1 genotype, do give some credence to a true effect. Certainly further work in this area is warranted.…”

Section: Challenging Issues In Ms Epidemiological Researchmentioning

confidence: 99%

The role of epidemiology in MS research: Past successes, current challenges and future potential

2015

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Multiple sclerosis (MS) is a multifaceted condition, with a range of environmental, behavioural and genetic factors implicated in its aetiology and clinical course. Successes in advancing our appreciation of the roles of Epstein-Barr virus, vitamin D/UV and the HLA-DRB1 locus; and our greater understanding of these and related factors' modes of action in MS and other conditions, can be attributed in no small part to the work of generations of epidemiologists. Hardly content to rest on our laurels, however, there are yet a range of unsolved conundrums in MS, including some changes in epidemiological characteristics (e.g. increasing incidence and sex ratio), to say nothing of the unresolved parts regarding what underlies MS risk and its clinical course. There is evidence that epidemiology will continue to play a crucial role in unravelling the architecture of MS causation and clinical course. While classic epidemiological methods are ongoing, novel avenues for research include gene-environment interaction studies, the world of '-omic' research, and the utilisation of mobile and social media tools to both access and track study populations, which means that the epidemiological discoveries of the past century may be but a glimpse of our understanding in the next few decades.

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HLA-DRB1 and month of birth in multiple sclerosis

Abstract: Month of birth, HLA-DRB1 genotype, and risk of multiple sclerosis are associated. The interaction of a seasonal risk factor with loci at or near HLA-DRB1 during gestation or shortly after birth is implicated.

Cited by 49 publications

References 26 publications

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

MHC transmission

The role of epidemiology in MS research: Past successes, current challenges and future potential

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