title: 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.
authors: Research Laboratory, Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya, Málaga, Spain.
authors: Carlos
authors: C
authors: López-Gómez
authors: Almudena
authors: A
authors: Pino-Ángeles
authors: Teresa
authors: T
authors: Órpez-Zafra
authors: María Jesús
authors: MJ
authors: Pinto-Medel
authors: Begoña
authors: B
authors: Oliver-Martos
authors: Jesús
authors: J
authors: Ortega-Pinazo
authors: Carlos
authors: C
authors: Arnáiz
authors: Cristina
authors: C
authors: Guijarro-Castro
authors: Jezabel
authors: J
authors: Varadé
authors: Roberto
authors: R
authors: Álvarez-Lafuente
authors: Elena
authors: E
authors: Urcelay
authors: Francisca
authors: F
authors: Sánchez-Jiménez
authors: Óscar
authors: Ó
authors: Fernández
authors: Laura
authors: L
authors: Leyva
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D058851:GPI-Linked Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D016899:Interferon-beta
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