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TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis.

Abstract

OBJECTIVES

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.

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  • Publisher Full Text
  • Authors

    , , , , , , , , , , , , , , ,

    Source

    Neurology 80:22 2013 May 28 pg 2010-6

    MeSH

    Adult
    Age Factors
    Age of Onset
    Alleles
    Cohort Studies
    Disease Progression
    Female
    Genetic Predisposition to Disease
    Genotype
    Humans
    Male
    Middle Aged
    Multiple Sclerosis
    Mutation
    Polymorphism, Genetic
    Receptors, Tumor Necrosis Factor, Type I
    Severity of Illness Index

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23624563

    Citation

    TY - JOUR T1 - TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis. AU - Comabella,Manuel, AU - Caminero,Ana B, AU - Malhotra,Sunny, AU - Agulló,Luis, AU - Fernández,Oscar, AU - Reverter,Ferran, AU - Vandenbroeck,Koen, AU - Rodríguez-Antigüedad,Alfredo, AU - Matesanz,Fuencisla, AU - Izquierdo,Guillermo, AU - Urcelay,Elena, AU - López-Larios,Arturo, AU - Sánchez,Alex, AU - Otero,Susana, AU - Tintoré,Mar, AU - Montalban,Xavier, Y1 - 2013/04/26/ PY - 2013/4/26/aheadofprint PY - 2013/4/30/entrez PY - 2013/4/30/pubmed PY - 2013/7/28/medline SP - 2010 EP - 6 JF - Neurology JO - Neurology VL - 80 IS - 22 N2 - OBJECTIVES: 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. SN - 1526-632X UR - https://www.unboundmedicine.com/medline/citation/23624563/full_citation L2 - http://www.neurology.org/cgi/pmidlookup?view=long&pmid=23624563 ER -