Inheritance mode of multiple sclerosis: the effect of HLA class II alleles is stronger than additive

Boon, Maartje; Nolte, Ilja M.; Keyser, Jacques De; Buys, Charles H.C.M.; Meerman, Gerard J. te

doi:10.1007/s00439-004-1169-8

Cited by 4 publications

(3 citation statements)

References 32 publications

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“…HLA-DRB1*15 heterozygotes have an increased risk of MS with an OR of 2.9 (Tables 1 and 7). The HLA-DRB1*15/15 offspring genotype also increases risk over HLA-DRB1*X/X by 5.4-fold, and is in keeping with an additive mode of inheritance for HLA-DRB1*15, similar to other studies [12,[18][19][20][21].…”

Section: Discussionsupporting

confidence: 87%

Suppressor Alleles in Multiple Sclerosis: Inheritance and Interactions

Ramagopalan¹,

Morris²,

Dyment³

et al. 2005

PLoS Genet

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Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLA-DRB1*17, implying that several mechanisms may be operative in major histocompatibility complex-associated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complex-associated susceptibility.

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Section: Discussionsupporting

confidence: 87%

Suppressor Alleles in Multiple Sclerosis: Inheritance and Interactions

Ramagopalan¹,

Morris²,

Dyment³

et al. 2005

PLoS Genet

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“…Following menopause, or when E2 levels are unusually low, suppression of MHC II and immune function is lost, allowing self-reactive T H 1 cells to become active and pathogenic. It is possible that estrogen and serotonin's modulation of the immune system prevents immune attack on offspring during pregnancy (when estrogen is at relatively high concentrations) and avoids infection after delivery (when estrogen is relatively low) [ 111 ].…”

Section: Discussionmentioning

confidence: 99%

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

et al. 2005

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BackgroundIn humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals.DiscussionWe hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone.SummarySerotonergic mediation of estrogen has important clinical implications and warrants further evaluation.

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“…The interaction of different MS susceptibility loci is already known and may lead to considerable MS-risk amplification [ 17 , 18 ]. The question of how ERV elements interfere with OCB associated loci and result in production of intrathecal OCB IgG remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Genetic Determinants of Antibody Levels in Cerebrospinal Fluid in Multiple Sclerosis: Possible Links to Endogenous Retroviruses

Emmer

Brütting

Kornhuber

et al. 2018

IJMS

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The pathogenesis of multiple sclerosis (MS) has not been clarified. In addition to environmental factors; genetic determinants have been implicated in the pathogenesis of MS. Furthermore, endogenous retroviruses (ERV) might play a role in MS. The presence of oligoclonal immunoglobulin in cerebrospinal fluid (CSF) is a typical feature of MS. Recently, genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS. The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame. In previous studies, we identified ERV sequences in the vicinity of MS associated SNPs. Here, we describe the identification of ERV sequences in the neighborhood of SNPs associated with CSF antibody levels. All of the identified SNPs are located in the vicinity of ERV sequences. One of these sequences has very high homology to a sequence derived from the so-called MS-associated retrovirus (MSRV). Another cluster of three ERV sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes. These observations might shed new light on a possible association between ERVs and MS pathogenesis.

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Inheritance mode of multiple sclerosis: the effect of HLA class II alleles is stronger than additive

Cited by 4 publications

References 32 publications

Suppressor Alleles in Multiple Sclerosis: Inheritance and Interactions

Suppressor Alleles in Multiple Sclerosis: Inheritance and Interactions

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

Genetic Determinants of Antibody Levels in Cerebrospinal Fluid in Multiple Sclerosis: Possible Links to Endogenous Retroviruses

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