TRAIL and TRAIL Receptor genes have been implicated in Multiple Sclerosis pathology as well as in the response to IFN beta
therapy. The objective of our study was to evaluate the association of these genes in relation to the age at disease onset
(AAO) and to the clinical response upon IFN beta treatment in Spanish MS patients. We carried out a candidate gene study
of TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 genes. A total of 54 SNPs were analysed in 509 MS patients under IFN
beta treatment, and an additional cohort of 226 MS patients was used to validate the results. Associations of rs1047275 in
TRAILR-2 and rs7011559 in TRAILR-4 genes with AAO under an additive model did not withstand Bonferroni correction. In
contrast, patients with the TRAILR-1 rs20576-CC genotype showed a better clinical response to IFN beta therapy compared
with patients carrying the A-allele (recessive model: p = 8.886 x 10-4, pc = 0.048, OR = 0.30). This SNP resulted in a non
synonymous substitution of Glutamic acid to Alanine in position 228 (E228A), a change previously associated with
susceptibility to different cancer types and risk of metastases, suggesting a lack of functionality of TRAILR-1. In order to
unravel how this amino acid change in TRAILR-1 would affect to death signal, we performed a molecular modelling with
both alleles. Neither TRAIL binding sites in the receptor nor the expression levels of TRAILR-1 in peripheral blood
mononuclear cell subsets (monocytes, CD4+ and CD8+ T cells) were modified, suggesting that this SNP may be altering the
death signal by some other mechanism. These findings show a role for TRAILR-1 gene variations in the clinical outcome of
IFN beta therapy that might have relevance as a biomarker to predict the response to IFN beta in MS.
; Ortega-Pinazo, Jesús; Arnáiz, Carlos; Guijarro-Castro, Cristina; Varadé, Jezabel; Alvarez-Lafuente, Roberto; Urcelay, Elena; Sánchez-Jiménez, Francisca María
