title: TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis.
abstract: OBJECTIVE
  To investigate the roles of 2 polymorphisms of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene, rs1800693 (a common variant) and rs4149584 (a coding polymorphism that results in an amino acid substitution-R92Q), as genetic modifiers of multiple sclerosis (MS), and to evaluate their potential functional implications in the disease.
  
  
  METHODS
  The effects of rs1800693 and rs4149584 on 2 measures of disease severity, age at disease onset and Multiple Sclerosis Severity Score, were analyzed in 2,032 patients with MS. In a subgroup of patients, serum levels of the soluble form of TNF-R1 (sTNF-R1) were measured by ELISA; mRNA expression levels of the full-length TNF-R1 and Δ6-TNF-R1 isoform were investigated in peripheral blood mononuclear cells (PBMC) by real-time PCR; cell surface expression of the TNF-R1 was determined in T cells by flow cytometry.
  
  
  RESULTS
  For rs4149584, R92Q carriers were younger at disease onset and progressed slower compared to noncarriers. However, no association with disease severity was observed for rs1800693. Serum levels of sTNF-R1 and mRNA expression levels of the full-length receptor were significantly increased in patients with MS carrying the R92Q mutation (p = 0.003 and p = 0.011, respectively), but similarly distributed among rs1800693 genotypes; cell surface TNF-R1 expression in T cells did not differ between rs4149584 and rs1800693 genotypes. The truncated soluble Δ6-TNF-R1 isoform was identified in PBMC from patients carrying the risk allele for rs1800693.
  
  
  CONCLUSIONS
  These findings suggest that both rs1800693 and rs4149584 TNFRSF1A polymorphisms have functional consequences in the TNF-R1.
authors.affiliation: Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d´Hebron, Barcelona, Spain. manuel.comabella@vhir.org
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.forename: Ana B
authors.initials: AB
authors.lastname: Caminero
authors.forename: Sunny
authors.initials: S
authors.lastname: Malhotra
authors.forename: Luis
authors.initials: L
authors.lastname: Agulló
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández
authors.forename: Ferran
authors.initials: F
authors.lastname: Reverter
authors.forename: Koen
authors.initials: K
authors.lastname: Vandenbroeck
authors.forename: Alfredo
authors.initials: A
authors.lastname: Rodríguez-Antigüedad
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Matesanz
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.forename: Arturo
authors.initials: A
authors.lastname: López-Larios
authors.forename: Alex
authors.initials: A
authors.lastname: Sánchez
authors.forename: Susana
authors.initials: S
authors.lastname: Otero
authors.forename: Mar
authors.initials: M
authors.lastname: Tintoré
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
mesh_terms: D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000483:Alleles; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human