title: Genetic variation in PBMC-produced IFN-γ and TNF-α associations with relapse in multiple sclerosis.
abstract: BACKGROUND
  Alterations in peripheral blood mononuclear cell (PBMC) cytokine production have been found in multiple sclerosis (MS) compared to healthy controls. We have previously found that stimulated PBMC-produced TNF-α and IFN-γ modulated MS relapse risk, such that raised TNF-α was protective, while raised IFN-γ increased relapse risk.
  
  
  OBJECTIVE
  To assess whether SNPs within genes for relevant cytokines and their receptors modulate the associations of TNF-α and IFN-γ with relapse, thus providing additional information about these cytokine effects and the roles of these genes in MS.
  
  
  METHODS
  Prospective cohort of 91 participants with relapsing-remitting MS and cytokine and genotype data. SNPs (N=361) within a window of 10 kb around each cytokine/cytokine receptor gene (N=84) were selected for analysis. Predictors of PBMC cytokines were evaluated by multilevel mixed-effects linear regression. Predictors of relapse were evaluated by Cox proportional hazards regression. Bonferroni correction was used to adjust for multiple testing; thus p<1.39 × 10(-4) was defined as significant.
  
  
  RESULTS
  Individuals of GG genotype of rs3218295 (within the gene IL2RB) demonstrated a significant protective effect of TNF-α on relapse while those of GA/AA genotype showed a significant positive association (pinteraction=5.04 × 10(-5)). Carriers of CC genotype of rs522807 (3' region of TNFRSF1B) and the AA genotype of rs25879 (5' region of IL3) showed a strong association between IFN-γ and increased relapse risk (pinteraction=8.21 × 10(-5) and 1.70 × 10(-5), respectively).
  
  
  CONCLUSIONS
  Our results show novel modulation of TNF-α and IFN-γ associations with relapse by SNPs in major cytokines. These findings suggest the potential for these genes and/or their products as potential therapeutic targets in MS.
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Australia.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Taylor
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Australia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Mei
authors.affiliation: School of Pharmacy, University of Tasmania, Australia; School of Medicine, University of Tasmania, Australia.
authors.forename: Niall
authors.initials: N
authors.lastname: Stewart
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Australia.
authors.forename: Jac
authors.initials: J
authors.lastname: Charlesworth
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Australia.
authors.forename: Leigh
authors.initials: L
authors.lastname: Blizzard
authors.affiliation: Murdoch Children's Research Institute, University of Melbourne, Australia.
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Ponsonby
authors.affiliation: Murdoch Children's Research Institute, University of Melbourne, Australia.
authors.forename: Terence
authors.initials: T
authors.lastname: Dwyer
authors.affiliation: School of Medicine, University of Tasmania, Australia.
authors.forename: Fotini
authors.initials: F
authors.lastname: Pittas
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Australia. Electronic address: steve.simpson@utas.edu.au.
authors.forename: Steve
authors.initials: S
authors.lastname: Simpson
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D055815:Young Adult
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Epidemiology; Interferon-gamma; Multiple sclerosis; Peripheral blood mononuclear cell; Relapse; Tumour necrosis factor alpha