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

PLoS One. 2013 Oct 10;8(10):e75565. doi: 10.1371/journal.pone.0075565. eCollection 2013.

Abstract

Objective: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain Stem / metabolism
  • Brain Stem / pathology
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology*
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Humans
  • Male
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / pathology*
  • Optic Neuritis / metabolism
  • Optic Neuritis / pathology
  • Polymorphism, Genetic / genetics*
  • Spinal Cord / metabolism
  • Spinal Cord / pathology

Grant support

This study was supported by a National Multiple Sclerosis Society research grant (www.nmss.org; RG-3692A; PI E. Waubant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.