OBJECTIVE: To investigate the effects of multiple sclerosis (MS) genetic susceptibility variants on gene expression and disease progression.
BACKGROUND: Large-scale studies identified single-nucleotide polymorphisms (SNPs) within the CD58 gene that are associated with MS. CD58 is a membrane protein expressed on antigen-presenting cells that functions in adhesion and activation of T-cells. However, it is largely elusive how these variants may increase the risk of MS and whether they correlate with individual disease activity and progression.
DESIGN/METHODS: With informed consent, blood samples were collected from 600 well characterized MS patients and 600 controls (163 males per group) from north-east Germany. Three different SNPs within the first intron of CD58 (rs12044852, rs1335532 and rs2300747) that tend to be inherited together were determined by TaqMan genotyping assays. Gene expression in peripheral blood mononuclear cells was quantified using microarrays for a subset of 57 interferon-beta-treated MS patients for which we have complete clinical follow-up information over a 5-year period. Measures of disease severity incorporated relapse rate and disability. We grouped the patients according to "good", "poor" and "very poor" therapy outcomes.
RESULTS: The strongest genetic association was seen for rs12044852 (odds ratio=2.13, Fisher9s exact test p-value=8.3*10^-07), followed by rs1335532 (OR=2.11, p=8.1*10^-08) and rs2300747 (OR=2.00, p=8.3*10^-07). The combination rs12044852 (C) and DRB1*15 (OR=3.35, p=1.5*10^-23) was more discriminative than DRB1*15 alone. Expression quantitative trait loci (eQTL) analysis revealed comparable CD58 mRNA levels among the different genotypes. At the genetic and at the gene expression level there was no significant association to disease subtype (relapsing vs. progressive) and long-term therapy outcome.
CONCLUSIONS: We confirmed MS-associated SNPs within CD58. These SNPs did not result in altered mRNA levels in vivo, and they were not suited for the prognosis of disease progression. Future studies may address in more detail the alternative splicing of CD58 to better understand its role in the pathophysiology of MS.
Study Supported by: Bayer HealthCare Disclosure: Dr. Heckerhas received personal compensation for activities with Bayer Pharmaceuticals Corp., Teva Neuroscience, and Novartis. Dr. Blaschke has nothing to disclose. Dr. Blaschke has nothing to disclose. Dr. Fitzner has nothing to disclose. Dr. Koczan has nothing to disclose. Dr. Thiesen has nothing to disclose. Dr. Zettl has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva.