Multiple sclerosis susceptibility and the X chromosome

Abstract

Multiple sclerosis (MS) is a chronic autoimmune complex trait with strong evidence for a genetic component. A female gender bias is clear but unexplained and a maternal parent-of-origin effect has been described. X-linked transmission of susceptibility has been previously proposed, based on pedigree, association and linkage studies. We genotyped 726 relative pairs including 552 affected sib-pairs for 22 X-chromosome microsatellite markers and a novel dataset of 195 aunt-uncle/niece-nephew (AUNN) affected pairs for 18 markers. Parent-of-origin effects were explored by dividing AUNN families into likely maternal and paternal trait transmission. For the sib-pair dataset we were able to establish exclusion at a s ϭ1.9 for all markers using an exclusion threshold of LOD ՅϪ2. Similarly for the AUNN dataset, we established exclusion at AV ϭ1.9. For the combined dataset we estimate exclusion of ϭ1.6. We did not identify significant linkage in either the sib-pairs or the AUNN dataset nor when datasets were stratified for the presence/absence of the HLA-DRB1*15 allele or for paternal or maternal transmission. This comprehensive scrutiny of the X-chromosome suggests that it is unlikely to harbour an independent susceptibility locus or one which interacts with the HLA. Complex interactions including epigenetic ones, and masking by balanced polymorphisms are mechanisms not excluded by the approach taken. Multiple Sclerosis 2007; 13: 856-864. http://msj.sagepub.com

Estrogen Controls Vitamin D3-Mediated Resistance to Experimental Autoimmune Encephalomyelitis by Controlling Vitamin D3 Metabolism and Receptor Expression

“…An increase in the female bias of MS has been observed in the United States (26,77), Canada (28,30), Australia (78), the United Kingdom (29,79), Norway (27,80), and Sardinia (81), due to an increased incidence among women, rather than to a decreased incidence among men. One explanation for the female bias could be X-linked risk factors, but extensive X chromosome linkage studies have not revealed MS susceptibility loci (82), and the rapidity of the femaleto-male sex ratio increase argues against a genetic origin (28). Another explanation for the female bias in MS invokes sex hormone-determined differences in immune responsiveness (25).…”

Vitamin D and Multiple Sclerosis

“…Extensive X-chromosome linkage studies have not revealed MS susceptibility loci, suggesting that X-linked risk factors probably do not explain the female sex bias [281]. Moreover, the three-fold increase in MS incidence among young women in the last half-century is not consistent with a genetic origin [270].…”

European Charcot Foundation Lecture: The natural history of multiple sclerosis and gender

“…A recent molecular genetics study using data from the CCPGSMS [60] looked at 552 sib-pairs and 195 aunt-uncle/niece-nephew (AUNN) pairs who were genotyped for 22 X-chromosome microsatellite markers as well as a novel dataset of 18 markers. Parent-of-origin effects were explored by dividing AUNN families into maternal and paternal.…”

“…Together, the combined dataset gave exclusion at λ = 1.6. The study [60] concluded the following with the caveat that complex interactions, including epigenetic ones and masking balanced polymorphisms could not be excluded by the study design:…”