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TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis.
Neurology 2013; 80(22):2010-6Neur

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.

Authors+Show Affiliations

Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d´Hebron, Barcelona, Spain. manuel.comabella@vhir.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

23624563

Citation

Comabella, Manuel, et al. "TNFRSF1A Polymorphisms Rs1800693 and Rs4149584 in Patients With Multiple Sclerosis." Neurology, vol. 80, no. 22, 2013, pp. 2010-6.
Comabella M, Caminero AB, Malhotra S, et al. TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis. Neurology. 2013;80(22):2010-6.
Comabella, M., Caminero, A. B., Malhotra, S., Agulló, L., Fernández, O., Reverter, F., ... Montalban, X. (2013). TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis. Neurology, 80(22), pp. 2010-6. doi:10.1212/WNL.0b013e318294b2d6.
Comabella M, et al. TNFRSF1A Polymorphisms Rs1800693 and Rs4149584 in Patients With Multiple Sclerosis. Neurology. 2013 May 28;80(22):2010-6. PubMed PMID: 23624563.
* Article titles in AMA citation format should be in sentence-case
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 - 2013/4/30/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/TNFRSF1A_polymorphisms_rs1800693_and_rs4149584_in_patients_with_multiple_sclerosis_ L2 - http://www.neurology.org/cgi/pmidlookup?view=long&pmid=23624563 DB - PRIME DP - Unbound Medicine ER -