RESEARCH - Smoking increases RA susceptibility in individuals carrying the HLA-DRB1 shared epitope

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Arthritis & Rheumatism

Volume 62, Issue 2, Pages 369-377

Published Online: 7 Jan 2010

Smoking increases rheumatoid arthritis susceptibility in individuals

carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor

or anti-cyclic citrullinated peptide antibody status

So-Young Bang 1, Kyoung-Ho Lee 2, Soo-Kyung Cho 1, Hye-Soon Lee 1,

Kyung Wha Lee 3, Sang-Cheol Bae 1 *

1Hospital for Rheumatic Diseases, Hanyang University, Seoul, South Korea

2Seoul National University, Seoul, South Korea

3Hallym Institute for Genome Application, Hallym University Sacred

Heart Hospital, Anyang, South Korea

Funded by:

Korea Healthcare Technology Research and Development Project,

Ministry for Health, Welfare and Family Affairs, Republic of Korea;

Grant Number: A084794

Abstract

Objective

Smoking is associated with rheumatoid arthritis (RA) in individuals

with the HLA-DRB1 shared epitope (SE). SE alleles have been shown to

be predominantly associated with anti-cyclic citrullinated peptide

(anti-CCP)-positive RA. These risk factors have not been identified

for anti-CCP-negative RA. The aim of this study was to investigate

whether SE-containing HLA-DRB1 alleles, smoking, or the combination of

these factors contributes to the development of RA, depending on the

presence or absence of serologic markers, in a Korean population.

Methods

All of the patients with RA (n =1,482) and all of the control subjects

(n = 1,119) were Korean. Four-digit HLA-DRB1 typing was performed by a

conventional polymerase chain reaction-sequence-based typing method.

Information about smoking history was obtained through a

questionnaire. The patients with RA were tested for anti-CCP

antibodies and rheumatoid factor (RF).

Results

The SE alleles had significant effects on anti-CCP antibody and RF

formation. The DRB1*0901 allele was associated with the presence of

anti-CCP antibodies (odds ratio [OR] 2.49) and RF (OR 2.09). SE

alleles and smoking were associated with both anti-CCP-positive and

anti-CCP-negative RA. The combination of smoking and double copies of

the SE allele increased the risk of anti-CCP-positive RA 36.11-fold

and increased the risk of anti-CCP-negative RA 12.29-fold, compared

with the risk among nonsmokers not carrying SE alleles. Interactions

between SE alleles and smoking were observed for both

anti-CCP-positive and RF-positive RA, although the associations of

RF-positive RA could be consequences of the underlying anti-CCP

antibody status.

Conclusion

We demonstrated that the combination of SE alleles and smoking is

associated with RA susceptibility regardless of anti-CCP antibody or

RF status, but that the combination shows stronger effects in

anti-CCP-positive/RF-positive patients with RA than in

anti-CCP-negative/RF-negative patients with RA. The SE-smoking

interactions were present in anti-CCP-positive and RF-positive RA.

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http://www3.interscience.wiley.com/cgi-bin/fulltext/123235521/HTMLSTART

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