A Glucocorticoid Receptor Gene Haplotype (TthIII1/ER22/23EK/9 beta) Is Associated with a More Aggressive Disease Course in Multiple Sclerosis

Context: 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 9 beta polymorphism, which is also associated with a relative GC resistance, were associated with a more aggressive disease course. Patients and Methods: Polymorphisms in the GR gene (9 beta, ER22/23EK, TthIIII, BcII, and N363S), which have previously been associated with altered GC sensitivity were determined and haplo-structure 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 9 beta-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 9 beta and TthIIII polymorphisms. Conclusions: MS patients carrying the haplotype 6 (TthIIII, ER22/23EK, and 9 beta) have a more aggressive disease course. This is probably due to the presence of the polymorphism ER22/23EK, which causes a decreased GC sensitivity. (J Clin Endocrinol Metab 94: 2110-2114, 2009)