title: A glucocorticoid receptor gene haplotype (TthIII1/ER22/23EK/9beta) is associated with a more aggressive disease course in multiple sclerosis.
abstract: BACKGROUND
  In patients with multiple sclerosis (MS), glucocorticoids (GCs) might not be sufficiently able to restrain the immune system, possibly due to decreased GC sensitivity. This may be, at least partially, genetically determined. Previously, we reported a more aggressive disease course in patients with the glucocorticoid receptor (GR) gene ER22/23EK polymorphism, which has been shown to decrease GC sensitivity.
  
  
  OBJECTIVE
  In 646 MS patients and 317 healthy controls, we investigated whether haplotypes, including the ER22/23EK polymorphism or the GR 9beta polymorphism, which is also associated with a relative GC resistance, were associated with a more aggressive disease course.
  
  
  METHODS
  Polymorphisms in the GR gene (9beta, ER22/23EK, TthIIII, BclI, and N363S), which have previously been associated with altered GC sensitivity were determined and haplostructure was characterized. We evaluated whether the haplotypes were associated with disease susceptibility and several other disease characteristics. The association with disease progression was analyzed using Cox regression with time to Expanded Disability Status Score 6 as outcome.
  
  
  RESULTS
  None of the haplotypes was associated with disease susceptibility, age at onset, or onset type. Haplotype 6 (TthIIII, ER2223EK, and 9beta-G) was associated with a more rapid disease progression (hazard ratio 2.3; 95% confidence interval 1.5-3.7; P < 0.001). This seems to result from the presence of ER22/23EK, and not from the 9beta and TthIIII polymorphisms.
  
  
  CONCLUSIONS
  MS patients carrying the haplotype 6 (TthIIII, ER22/23EK, and 9beta) have a more aggressive disease course. This is probably due to the presence of the polymorphism ER22/23EK, which causes a decreased GC sensitivity.
authors.affiliation: Department of Neurology, Vrije Universiteit Medical Center, P.O. Box 7057, Amsterdam 1007 MB, The Netherlands. L.vanWinsen2@vumc.nl
authors.forename: Lisa M L
authors.initials: LM
authors.lastname: van Winsen
authors.forename: Laura
authors.initials: L
authors.lastname: Manenschijn
authors.forename: Elisabeth F C
authors.initials: EF
authors.lastname: van Rossum
authors.forename: J Bart A
authors.initials: JB
authors.lastname: Crusius
authors.forename: Bart A
authors.initials: BA
authors.lastname: Crusius
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Koper
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.forename: Bernard M J
authors.initials: BM
authors.lastname: Uitdehaag