Multiple Sclerosis Susceptibility Genes: Associations with Relapse Severity and Recovery

Abstract

ObjectivePatients with early multiple sclerosis (MS) have stereotyped attack severity and recovery. We sought to determine if polymorphisms in MS susceptibility genes are associated with these attack features or with the risk of a second attack.Methods503 white subjects evaluated within a year of MS onset were included in the study. The severity of and recovery from the first two attacks were determined based on published definitions. Seventeen MS susceptibility genes were genotyped at the UCSF MS Genetics laboratory. Each polymorphism was evaluated in multivariate ordinal models, adjusted for the other polymorphisms, for its association with attack severity and recovery. We also assessed if these polymorphisms were associated with increased risk of a second attack.ResultsThe MPHOSPH9 polymorphism was associated with greater attack severity (odds ratios [OR] = 1.47, 95% CI [1.11, 1.94], p = 0.008), while the RGS1 and TNFRSF1A polymorphisms tended to be associated with reduced attack severity. The CD6 polymorphism tended to be associated with increased odds of worse attack recovery (OR = 1.25, 95% CI [0.93, 1.68], p = 0.13). In those who were HLA-DRB1-negative, the EVI5 polymorphism was associated with attacks of less severity; in HLA-DRB1 positive patients, EVI5 was associated with attacks of greater severity and worse recovery. The IL7R, TNFRSF1A, and GPC5 polymorphisms tended to be associated with having a second event within a year.ConclusionsSome MS susceptibility polymorphisms may be associated with attack severity, recovery, or frequency. Further characterization of these genes may lead to a better understanding of MS pathogenesis and to a more individualized treatment approach.

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

“…In contrast, a study in Belgians reported a not quite significant trend towards a more severe disease in A allele carriers (Goris et al, ), whereas a study in the Spanish population detected an association of A allele with lower MS severity and lower age at MS onset (Comabella et al, ). Finally, a prospective study in patients of European ancestry found that A allele carriers have tendencies for reduced attack severity and for having a second event within a year (Mowry et al, ).…”

Multiple Sclerosis Relapses: Epidemiology, Outcomes and Management. A Systematic Review

“…It was previously reported that the major histocompatibility locus that has the strongest association with susceptibility to MS, HLA-DRB1 * 1501, may also be associated with the probability of conversion to definite MS in patients with a CIS [49] . In another study, three susceptibility loci were associated with relapse severity: MPHOSPH9 positively, and RGS1 and TNFRSF1A negatively [50] . In contrast, other studies did not find any associations between the relapse hazard and the known loci of MS susceptibility [51][52][53] .…”

Environmental and genetic risk factors for MS: an integrated review

“…Though overall susceptibility genes do not appear to have large effects on phenotype, there is some evidence that HLA and non‐HLA genetic risk factors may alter relapse rates, although overall findings are mixed and weak. Some susceptibility polymorphisms have been associated with attack or MRI lesion location and severity . The strongest genetic factor ( HLA‐DRB1*15:01 ) has been associated with earlier age of onset and possibly with greater deep gray matter atrophy .…”