TY - JOUR
T1 - Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis
AU - Mahdi, Hiba
AU - Fisher, Benjamin A
AU - Källberg, Henrik
AU - Plant, Darren
AU - Malmström, Vivianne
AU - Rönnelid, Johan
AU - Charles, Peter
AU - Ding, Bo
AU - Alfredsson, Lars
AU - Padyukov, Leonid
AU - Symmons, Deborah P M
AU - Venables, Patrick J
AU - Klareskog, Lars
AU - Lundberg, Karin
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.1038/ng.480
DO - 10.1038/ng.480
M3 - Article
C2 - 19898480
SN - 1546-1718
VL - 41
SP - 1319
EP - 1324
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -