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

Multiple Sclerosis Center, Department of Neurology, Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS ONE (Impact Factor: 3.23). 10/2013; 8(10):e75565. DOI: 10.1371/journal.pone.0075565
Source: PubMed


The 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.
17 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).
The 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.
Some 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.

Download full-text


Available from: Emmanuelle Waubant, Mar 07, 2014
38 Reads
    • "Most prior genetic association studies focus on MS susceptibility, rarely examining genetic influences on MS phenotype and initial symptoms . One recent study identified several known MS susceptibility genes that impact the early CNS attack location (Mowry et al., 2013). However, among analysed predictors of optic nerve involvement, only the CD6 polymorphism conferred reduced odds of ON as an attack location , and no significant associations with other polymorphisms were found. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies show altered activities of matrix metalloproteinase (MMP)-2 and MMP-9 in serum and cerebrospinal fluid of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients. Optic neuritis (ON) is a common symptom of both disorders. Here we investigated the impacts of MMP-2 -1575G/A and MMP-9 -1562 C/T gene polymorphisms on disease phenotype in 100 MS patients with ON as a first symptom and 376 MS patients with other initial symptomatology. The MMP-2 -1575G/A polymorphism led to a 5-year-earlier age of disease onset in MS patients with ON as a first symptom (p=0.009). Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of neuroimmunology 09/2015; 286:13-15. DOI:10.1016/j.jneuroim.2015.06.014 · 2.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10(-14)). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
    Multiple Sclerosis 04/2014; 20(11). DOI:10.1177/1352458514528762 · 4.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is a neurological immune-driven disease of unknown etiology. A genetic contribution to MS susceptibility is well established and more than 100 associated genomic regions have been identified. However, there is little understanding of how individual genetic variants are involved in the pathogenesis of MS. Single nucleotide polymorphisms (SNPs) within the first intron of CD58 have been independently confirmed to be related to the risk of MS. We here provide evidence that these SNPs may implicate an altered processing of an intronic microRNA. This microRNA, hsa-mir-548ac, belongs to a huge primate-specific family of microRNAs that evolved from a mariner-derived transposable element (Made1). Sequencing data of the 1000 Genomes project revealed a SNP, rs1414273, at the base of the microRNA stem-loop to be in strong linkage disequilibrium with the MS-associated haplotype. This SNP is suspected to affect the recognition of the primary microRNA hairpin by Drosha and its cofactor DGCR8. Future studies on microRNA-548ac and its genetic variant may yield deeper insights into the mechanisms underlying MS. Experimental challenges and open questions are discussed. Copyright © 2014 Elsevier B.V. All rights reserved.
    Mutation Research/Reviews in Mutation Research 10/2014; 763. DOI:10.1016/j.mrrev.2014.10.002 · 6.21 Impact Factor