Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis.
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.
Mahdi
Hiba
H
Rheumatology Unit, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden.
Fisher
Benjamin A
BA
Källberg
Henrik
H
Plant
Darren
D
Malmström
Vivianne
V
Rönnelid
Johan
J
Charles
Peter
P
Ding
Bo
B
Alfredsson
Lars
L
Padyukov
Leonid
L
Symmons
Deborah P M
DP
Venables
Patrick J
PJ
Klareskog
Lars
L
Lundberg
Karin
K
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
D001323:Autoantibodies; D002956:Citrulline; D010751:Phosphopyruvate Hydratase