Association of Multiple Sclerosis Susceptibility Variants and Early Attack Location in the CNS

Abstract

ObjectiveThe anatomic location of subsequent relapses in early multiple sclerosis (MS) appears to be predicted by the first attack location. We sought to determine if genetic polymorphisms associated with MS susceptibility are associated with attack location.Methods17 genome-wide association study-identified MS susceptibility polymorphisms were genotyped in 503 white, non-Hispanic patients seen within a year of MS onset. Their association with the CNS location of the first two MS attacks was assessed in multivariate repeated measures analyses (generalized estimating equations with robust standard errors).ResultsThe IL12A polymorphism was independently associated with increased odds of attacks involving the spinal cord (OR = 1.52, 95% CI 1.11, 2.07, p = 0.009), as was the IRF8 polymorphism (OR = 2.40, 95% CI [1.04, 5.50], p = 0.040). The IL7R polymorphism was associated with reduced odds of attacks involving the brainstem/cerebellum (OR = 0.46, 95% CI 0.22, 0.97, p = 0.041), as were the TNFRSF1A and IL12A polymorphisms. The CD6 polymorphism conferred reduced odds of optic neuritis as an attack location (OR = 0.69, 95% CI [0.49, 0.97], p = 0.034). Several other genes showed trends for association with attack location.ConclusionsSome of the MS susceptibility genes may be associated with MS attack location. The IL12A polymorphism is of particular interest given that interferon beta therapy appears to influence IL12 levels. These findings may lead to improved understanding of MS pathogenesis and treatment.

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 .…”

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

“…In fact, studies showed that areas of demyelination are commonly localised within previously remyelinated regions [109,110] . This inherent predisposition is likely to be determined by numerous polygenic factors, including genetic factors, such as some of the MS susceptibility factors [111] , several genes involved in the regulation of immune cell function, myelin and neural growth [112] , and genetically correlated CD4 T-cell immunoreactivity [113] .…”

Meta-Analysis on Associations of RGS1 and IL12A Polymorphisms with Celiac Disease Risk

“…rs17810546 locates in a ~70-kb LD block, which is immediately 5′ of IL12A. Similar with the locus RGS1, IL12A has been reported with risk of MS and T1D, confirming the shared genetic factors among different autoimmune diseases [ 22 , 25 ]. In addition, a meta-analysis by Kappen et al [ 26 ] identified the genome wide significance association between IL12A rs17810546 and Behcet’s disease, which was also regarded as a Th1 mediated autoimmune disease.…”