Interaction of HLA-DRB1 shared epitope and smoking on the development of anti-citrullinated protein antibody positive rheumatoid arthritis in Greek patients.

OBJECTIVES

Rheumatoid arthritis (RA) is a complex, multifactorial autoimmune disease, whose aetiopathogenesis involves genetic and environmental factors. The aim of this case-control study is to confirm the impact of interaction of genetic and environmental factors in the pathogenesis of RA in Greek smoker and non-smoker patients.

METHODS

We assessed the effects of shared epitope (SE) alleles and smoking on the presence of ACPA autoimmunity in three hundred Greek patients with longstanding RA (150 smokers and 150 non-smokers). Three hundred and forty-six Greek blood donors volunteers and hospital personnel served as controls.

RESULTS

An increased frequency of HLA-DRB1 *01:01, *10:01, *04:04 and *04:05 alleles, as well as the protective role of *04:03 allele in Greek patients were confirmed during comparison with controls. The presence of any SE influenced the development of RA (OR: 4.37[3.13-6.11], p<0.001). A strong effect for ACPA production was observed in individuals carrying any SE allele (OR: 4.3[2.57-7.22], p<0.001). Single SE carriers in combination with smoking had an increased risk of developing ACPA-positive RA (OR: 6.53[1.47-28.91], p=0.013), which further increased in smokers with a double gene copy (OR: 15.27[1.39-167.52], p=0.026). The strongest interaction, with regard to ACPA-positive RA, was observed in individuals that possessed the HLA-DRB1 *01:01 (OR: 12.55[1.32-119.35], p=0.028) SE allele, whereas the combination of SE genes and smoking did not influence the risk of ACPA-negative RA (OR: 2.01[0.76-5.26], p=0.15).

CONCLUSIONS

We identified that smoking and the presence of SE alleles increased the risk of developing ACPA-positive RA, indicating a strong genetic-environmental correlation that probably triggers the pathogenesis of RA in Greek patients.