title: Different gene loci within the HLA-DR and TNF regions are independently associated with susceptibility and severity in Spanish rheumatoid arthritis patients.
abstract: The aim of this study was to investigate whether polymorphisms in the tumor necrosis factor (TNF) and HLA-DRB1 gene regions are independently associated with rheumatoid arthritis (RA) in a population from Lugo region of northwestern Spain. RA patients (n=179) attending hospital outpatient clinics in Lugo, northwestern Spain and matched controls (n=145) were recruited. RA susceptibility in this population was predominantly associated with DRB1*0401, while erosive disease was associated with HLA-DRB1*0101 and DRB1*04. The increase in DRB1*04 was accounted for by an increase in DRB1*0404 and *0405 but not *0401 frequencies. In contrast, *0401 frequency was significantly increased in seropositive patients. The rheumatoid arthritis shared epitope (SE) was associated with increased risk for seropositive and erosive disease and this appeared to operate in a dose-dependent manner. Logistic regression analyses revealed that the TNF microsatellite markers TNFc1 and b3 were associated with RA independently of DRB1*04 and the SE. Carriage of a TNF c1 allele provided an increased risk of RA in SE-negative and SE-heterozygous individuals. TNFc1 and TNFb3 were not associated with erosive or seropositive disease. In contrast, TNF a2 was significantly associated with erosive disease which was independent of DRB1*04 and the SE. Further studies will be needed to establish why (TNFc1) polymorphism seemingly associated with low TNFalpha production, is a risk factor for RA.
authors.affiliation: ARC Epidemiology Unit, School of Epidemiology and Health Sciences, Manchester University Medical School, United Kingdom. Ali.Hajeer@man.ac.uk
authors.forename: A H
authors.initials: AH
authors.lastname: Hajeer
authors.forename: A
authors.initials: A
authors.lastname: Dababneh
authors.forename: R F
authors.initials: RF
authors.lastname: Makki
authors.forename: W
authors.initials: W
authors.lastname: Thomson
authors.forename: K
authors.initials: K
authors.lastname: Poulton
authors.forename: M A
authors.initials: MA
authors.lastname: González-Gay
authors.forename: C
authors.initials: C
authors.lastname: García-Porrúa
authors.forename: D L
authors.initials: DL
authors.lastname: Mattey
authors.forename: W E
authors.initials: WE
authors.lastname: Ollier
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D013030:Spain; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D006684:HLA-DR Antigens; D014409:Tumor Necrosis Factor-alpha