title: Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis.
abstract: Gene-environment associations are important in rheumatoid arthritis (RA) susceptibility, with an association existing between smoking, HLA- DRB1 'shared epitope' alleles, PTPN22 and antibodies to cyclic citrullinated peptides (CCP). Here, we test the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of these associations. In 1,497 individuals from three RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43-63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 and smoking showed the strongest association with the anti-CEP-1-positive subset (odds ratio (OR) of 37, compared to an OR of 2 for the corresponding anti-CEP-1-negative, anti-CCP-positive subset). We conclude that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of RA.
authors.affiliation: Rheumatology Unit, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden.
authors.forename: Hiba
authors.initials: H
authors.lastname: Mahdi
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fisher
authors.forename: Henrik
authors.initials: H
authors.lastname: Källberg
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
authors.forename: Johan
authors.initials: J
authors.lastname: Rönnelid
authors.forename: Peter
authors.initials: P
authors.lastname: Charles
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Deborah P M
authors.initials: DP
authors.lastname: Symmons
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Venables
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Karin
authors.initials: K
authors.lastname: Lundberg
mesh_terms: D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D016022:Case-Control Studies; D002956:Citrulline / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D010751:Phosphopyruvate Hydratase / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects
chemical_list: D001323:Autoantibodies; D002956:Citrulline; D010751:Phosphopyruvate Hydratase