Candidate Gene Study of TRAIL and TRAIL Receptors: Association with Response to Interferon Beta Therapy in Multiple Sclerosis Patients

Abstract

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 = 8.88×10−4, 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.

Promotion of TRAIL/Apo2L‐induced apoptosis by low‐dose interferon‐β in human malignant melanoma cells

“…Recently, the association of TRAIL and TRAIL receptors to IFN‐β induced apoptosis has been reported. TRAIL and TRAIL‐R1 gene variation associated with the clinical outcome of IFN‐β therapy in multiple sclerosis patients (Hebb, Moore, Bhan, & Robertson, ; Lopez‐Gomez et al, ). TRAIL messenger RNA (mRNA) levels were increased in monocytes from patients clinically responsive to IFN‐β (Hebb et al, ).…”

Association of EGFR and KRAS mutations with expression of p-AKT, DR5 and DcR1 in non-small cell lung cancer

“…Tumor necrosis factor superfamily (TNFSF) plays an important role in the induction of apoptosis. TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL-R are the essential ligand and its associated receptors of TNFSF, respectively [11]. TRAIL combines with death receptors DR4 and DR5, and initiates apoptosis.…”