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.
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 rs4149584TNFRSF1A polymorphisms have functional consequences in the TNF-R1.
Authors: Linda Ottoboni; Irene Y Frohlich; Michelle Lee; Brian C Healy; Brendan T Keenan; Zongqi Xia; Tanuja Chitnis; Charles R Guttmann; Samia J Khoury; Howard L Weiner; David A Hafler; Philip L De Jager Journal: Neurology Date: 2013-10-30 Impact factor: 9.910
Authors: Assunta De Rienzo; Michael A Archer; Beow Y Yeap; Nhien Dao; Daniele Sciaranghella; Antonios C Sideris; Yifan Zheng; Alexander G Holman; Yaoyu E Wang; Paola S Dal Cin; Jonathan A Fletcher; Renee Rubio; Larry Croft; John Quackenbush; Peter E Sugarbaker; Kiara J Munir; Jesse R Battilana; Corinne E Gustafson; Lucian R Chirieac; Soo Meng Ching; James Wong; Liang Chung Tay; Stephen Rudd; Robert Hercus; David J Sugarbaker; William G Richards; Raphael Bueno Journal: Cancer Res Date: 2015-11-10 Impact factor: 12.701