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Smoking interacts with HLA-DRB1 shared epitope in the development of ACPA-positive rheumatoid arthritis: a case-control study from Malaysian epidemiological investigation of rheumatoid arthritis (MyEIRA)
  1. Chun-Lai Too1,2,
  2. Abqariyah Yahya2,3,
  3. Shahnaz Murad2,
  4. Jasbir Singh Dhaliwal2,
  5. Per Larsson1,
  6. Nor Asiah Muhamad2,
  7. Nor Aini Abdullah2,
  8. Amal Nasir Mustafa2,
  9. Lars Klareskog1,
  10. Lars Alfredsson3,
  11. Leonid Padyukov1,
  12. Camilla Bengtsson3
  1. 1Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  2. 2Institute for Medical Research, Jalan Pahang, Kuala Lumpur, Malaysia
  3. 3Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden


Backgroundand objectives To investigate whether smoking and HLA-DRB1 shared epitope (SE) alleles may interact differently in the development of the two major subgroups of rheumatoid arthritis (RA), anti-citrullinated proteins antibody (ACPA)-positive and ACPA-negative disease, in a multiethnic population of Asian descent.

Methods A case-control study with early diagnosed RA cases was performed in Malaysia between 2005 and 2009. In total, 1056 cases and 1416 matched controls participated in the study. High resolution HLA-DRB1 genotyping was performed for shared epitope (SE) alleles. All participants answered a questionnaire on a broad range of issues, including smoking habits. Possible interaction between smoking habits (defined as ‘ever’ and ‘never’ smoking) and DRB1-SE alleles was calculated.

Results In our multiethnic study, both the SE alleles and smoking were associated with an increased risk of developing ACPA-positive RA (OR SE alleles=5.2 (95% CI 4.3 to 6.4); OR smoking=2.2 (95% CI 1.6 to 3.2)). Smokers carrying SE alleles had an odds ratio of ACPA-positive RA of 24 (95% CI 9.9 to 56.2), compared with never-smokers without SE alleles. The interaction between smoking and SE alleles was significant, as measured by the attributable proportion due to interaction, which was 0.7 (95% CI 0.5 to 0.9).The combination of smoking and DRB1*0405 SE allele was significantly associated with ACPA-positive RA (OR=10.0 (95% CI 3.9 to 25.9); AP=0.3 (95% CI −0.3 to 0.9)). A very strong interaction between smoking and SE alleles was however, observed for all other non-DRB1*0405 SE alleles taken as a group in coffering risk of ACPA-positive (OR=63.0 (95% CI 8.1 to 491.3); AP=0.9 (0.8 to 1.1)). The combination of smoking and SE alleles was not associated with an increased risk in ACPA-negative RA.

Conclusion The risk of developing ACPA-positive RA is associated with a strong gene-environment interaction between smoking and HLA-DRB1 SE alleles in a multiethnic population of Asian descent from Malaysia.

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