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Associations between genetic factors, tobacco smoking and autoantibodies in familial and sporadic rheumatoid arthritis

¹ GenHotel-EA 3886, Universités Evry-ParisVII, Evry-Genopole, France
² Fédération de rhumatologie, Hôpital Lariboisière, Pôle appareil locomoteur, Assistance Publique-Hôpitaux de Paris, Paris, France
³ Faculty of Medicine, University of Coimbra, Coimbra, Portugal
⁴ Unité de Génétique Clinique Adulte, Hôpital Lariboisière, Pôle biologie-imagerie-pharmacie, Assistance Publique-Hôpitaux de Paris, France
⁵ Service de rhumatologie, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, France
⁶ Laboratoire Statistique et Génome, Evry-Genopole, France
⁷ Consultation de Génétique Adulte, Centre Hospitalier Sud Francilien, Evry-Corbeil, France

Correspondence to:
Laëtitia Michou, GenHotel-EA 3886, Laboratoire de Recherche Européen pour la Polyarthrite Rhumatoïde, ECRAF-Université Paris 7-Université d’Evry, 2 rue Gaston Crémieux, CP 5727, 91057 Evry-Genopole cedex, France; michou{at}polyarthrite.net

Objectives: The objective of this study was to investigate the association between genes (HLA-DRB1 and PTPN22) and tobacco smoking, separately as well as combined, and serological markers of rheumatoid arthritis (RA) in a French population with RA.

Methods: 274 patients with RA with half of them belonging to RA multicase families, were genotyped for HLA-DRB1 allele and for PTPN22-1858 polymorphism. IgM rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies were determined by ELISA method. The search for association relied on ² test and odds ratio with 95% confidence interval calculation. The interaction study relied on the departure-from-additivity-based method.

Results: The presence of at least one shared epitope (SE) allele was associated with anti-CCP antibodies presence (82.5% vs. 68.4%, p = 0.02), particularly with HLA-DRB1*0401 allele (28.0% vs. 16.4%, p = 0.01). Tobacco exposure was associated with anti-CCP antibodies, but only in presence of SE. A tendency toward an interaction was found between tobacco, the presence of at least one HLA-DRB1*0401 allele and anti-CCP antibodies (attributable proportion due to interaction = +0.24 (–0.21+0.76)). The cumulative dose of cigarette smoking was correlated with anti-CCP antibody titres (r = 0.19, p = 0.04). The presence of both SE and 1858T alleles was associated with a higher, but not significantly different, risk for anti-CCP antibodies presence than for each separately. No association was found between PTPN22-1858T allele and tobacco smoking for autoantibody positivity.

Conclusions: Our findings suggest an association between SE alleles and tobacco smoking for anti-CCP positivity and a tendency toward an interaction between the HLA-DRB1*0401 allele and smoking for anti-CCP positivity in this sample of RA.