title: Investigation of genetic variants within candidate genes of the TNFRSF1B signalling pathway on the response to anti-TNF agents in a UK cohort of rheumatoid arthritis patients.
abstract: The introduction of anti-tumour necrosis factor (TNF) agents has greatly improved the treatment of rheumatoid arthritis; however, a significant proportion of patients fail to respond to therapy. We hypothesized that genes within the TNF receptor superfamily member 1B signalling pathway contribute towards the observed variation in patient response. This was tested by genotyping 73 single-nucleotide polymorphisms (SNPs) from six candidate genes (DUSP1, HRB, IKBKAP, MAP3K1, MAP3K14 and TANK) in a large UK cohort of rheumatoid arthritis patients (n=642). Two SNPs [rs96844 (MAP3K1) and rs4792847 (MAP3K14)] showed evidence of association (P<0.05) to treatment response and were subsequently examined in an independent cohort of patients (n=428). Replication of association to either SNP was not achieved, but combined analysis of the complete cohort (n=1070) provided nominal evidence of association to both SNPs. We conclude that analysis of the common variation in the selected candidate genes did not provide strong evidence to implicate their involvement in varying patient response to anti-TNF treatment.
authors.affiliation: Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK. j.bowes@manchester.ac.uk
authors.forename: John D
authors.initials: JD
authors.lastname: Bowes
authors.forename: Catherine
authors.initials: C
authors.lastname: Potter
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gibbons
authors.forename: Kimme
authors.initials: K
authors.lastname: Hyrich
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
mesh_terms: D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics*; D015398:Signal Transduction; D006113:United Kingdom
chemical_list: D018501:Antirheumatic Agents; D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human