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Neurology. 2013 May 28;80(22):2010-6. doi: 10.1212/WNL.0b013e318294b2d6. Epub 2013 Apr 26.

TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis.

Author information

1
Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d´Hebron, Barcelona, Spain. manuel.comabella@vhir.org

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.

PMID:
23624563
DOI:
10.1212/WNL.0b013e318294b2d6
[Indexed for MEDLINE]

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