Journal
NATURE GENETICS
Volume 41, Issue 12, Pages 1319-U84Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.480
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Funding
- Arthritis Research Campaign
- Swedish Research Council
- Swedish Council for Working Life and Social Research
- Arbetsmarknadens Frs krings Aktibebolag insurance foundation
- US National Institutes of Health [P60 AR047782]
- FAMRI (Flight Attendants Medical Research Institute)
- Swedish Rheumatism Association
- King Gustav V's 80-year foundation
- Swedish Fund for Research
- EU funded research project AutoCure
- National Institute for Health Research [CL-2008-21-015] Funding Source: researchfish
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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)(1,2). Here, we test the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated.-enolase(3,4), 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(4) 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.
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