Specific interaction between genotype, smoking and autoimmunity to citrullinated α-enolase in the etiology of rheumatoid arthritis

Hiba Mahdi, Benjamin A. Fisher, Henrik Källberg, Darren Plant, Vivianne Malmström, Johan Rönnelid, Peter Charles, Bo Ding, Lars Alfredsson, Leonid Padyukov, Deborah P M Symmons, Patrick J. Venables, Lars Klareskog, Karin Lundberg

    Research output: Contribution to journalArticlepeer-review

    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 α-enolase, accounts for an important portion of these associations. In 1,497 individuals from three RA cohorts, antibodies to the immunodominant citrullinated α-enolase CEP-1 epitope were detected in 43-63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB104. 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 α-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of RA. © 2009 Nature America, Inc. All rights reserved.
    Original languageEnglish
    Pages (from-to)1319-1324
    Number of pages5
    JournalNature Genetics
    Volume41
    Issue number12
    DOIs
    Publication statusPublished - Dec 2009

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