MHC transmission

Abstract

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.

HLA-DRB1*1101 allele confer protection for Multiple Sclerosis disease in Cuban population

“…16,17 The selection of these particular alleles was based on previous studies in which they have been reported to be implicated as part of haplotypes conferring the highest risk or protection scores5. 18 Brief description: DRB1* 0401-0411-0301-1501-1502 -0101-0103 -0102 -0701-0702 -1001 -1101-1104 -1401-1404 1403, DQB1* 0602, DQA1* 0301, *0102. A primer pair to amplify the third intron of DRB1 genes was included in each PCR reaction as the internal positive control.…”

“…These two primers matched non-allelic sequence. 17,18 All primers were obtained from the Department of oligonucleotide synthesis, at Center of Genetic Engineering and Biotechnology (Havana, Cuba), and used at 0.25 µM. Amplified products were separated by electrophoresis in 2 % agarose gels containing ethidium bromide after the addition of loading buffer, and visualized using UV illumination.…”

Epigenetics in multiple sclerosis

“…19 In subsequent studies, interestingly, the major MS risk allele human leukocyte antigen (HLA)-DRB1*15 was found to be preferentially transmitted from mothers to affected female offspring. [20][21][22][23] These studies suggested that this preferential maternal transmission of the major histocompatibility complex (MHC) risk allele is the molecular basis of the maternal parent-of-origin effect in MS, and emphasized the involvement of epigenetic mechanisms in MS heritability. [20][21][22][23] These findings are quite solid, and the idea is attractive in that part of the missing heritability of MS can be explained by epigenetics.…”

“…[20][21][22][23] These studies suggested that this preferential maternal transmission of the major histocompatibility complex (MHC) risk allele is the molecular basis of the maternal parent-of-origin effect in MS, and emphasized the involvement of epigenetic mechanisms in MS heritability. [20][21][22][23] These findings are quite solid, and the idea is attractive in that part of the missing heritability of MS can be explained by epigenetics. However, the molecular basis for the parent-of-origin effect in MS, and how epigenetic mechanisms can skew not only the transmission of phenotype, but also the MHC genotype is not clear.…”

The use of multiple population-based data sources for estimating MS sex ratio trends over time

“…Underlying gender-related factors might be hormonal or environmental or due to gene-environment interactions. 9 Changes in women's lifestyle (i.e. use of contraceptives, dietary changes, obesity, smoking behaviour, roles in the workforce, sunlight exposure, vitamin D deficiency) and in particular higher age at first childbirth or fewer pregnancies could contribute to the increasing incidence of MS in women.…”