Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


The Gene-Environment Interaction between HLA-SE and Smoking Plays an Important Role in Shaping the Reactivity of the ACPA Response to Several Citrullinated Antigens.

Willemze2,  Annemiek, Woude3,  Diane van der, Alemayehu1,  Wendim Ghidey, de Vries4,  René R. P, Huizinga3,  Tom W. J., Trouw3,  Leendert A., Toes3,  René E. M

Leiden University Medical Center, Department of Medical Statistics
Leiden University Medical Center, Department of Rheumatology, Leiden, The Netherlands
Leiden University Medical Center, Department of Rheumatology
Leiden University Medical Center. Department of Immunohematology and Blood Transfusion

Objective:

Rheumatoid arthritis is a complex genetic disorder. Human leucocyte antigen shared epitope (HLA SE) alleles are the strongest genetic risk factor for anti-citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). It has recently been postulated that a specific interaction exists between genotype, smoking and autoimmunity to a peptide from enolase. We showed recently that this is not specific for citrullinated a-enolase, but also for a peptide derived from citrullinated vimentin. The aim of this study was to further expand these findings by investigating if gene-environment interactions affect the reactivity pattern to other citrullinated antigens as well.

Methods:

The reactivity of 766 RA patients to cyclic citrullinated peptide (CCP) and to four citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib), linear Enolase (cEnolase=C6lin) and Myelin Basic Protein (cMBP=anti-SA) was determined by enzyme-linked immunosorbent assay (ELISA). The separate effects of the HLA SE alleles and smoking were assessed by logistic regression analysis. Biologic interaction was analyzed by investigating if the effects of the risk factors combined exhibited departure from additivity.

Results:

The ACPA reactivity profile was affected by a significant biological interaction between the HLA SE alleles and smoking. Both the separate effects of HLA SE alleles and smoking, as well as their combined effects were present for anti-cVim, anti-cEnolase, anti-cMBP and anti-cFib. This effect was strongest for anti-cVim with an odds ratio (OR) of 41 (95% CI 14.7–118.5) in the anti-cVim-positive subset for smokers who were homozygous for the HLA SE alleles, compared to an OR of 6.2 (95% CI 2.4–16.1) in the anti-cVim-negative subset. For anti-enolase, this resulted in an OR of 40.0 (95% CI 11.4–135.2) in the positive subset and an OR of 10.1 (95% CI 4.2–24.2) in the negative group. Anti-MBP and Anti-cFib resulted in a more modest effect in interaction for smokers who were homozygous for SE (see table 1). Combining anti-cVim positive and anti-cEnolase positive patients that were homozygous for HLA SE and smokers, resulted in an even higher OR of 160.0 (95% CI 18.6–1373.0) compared to the anti-cVim negative and anti-cEnolase negative subset with an OR of 5.4 (95% CI 1.9–15.3).

Table 1. Interaction between HLA SE alleles, smoking and autoimmunity to various citrullinated peptides in RA patients

 HLA SE positive and smokerHLA SE homozygous and smoker
 OR(95% CI)OR(95% CI)
CCP2-1.0(ref)1.0(ref)
CCP2+7.7(4.7–12.4)14.5(6.4–33.0)
CCP2+cVim+18.0(8.2–39.7)41.7(14.7–118.5)
CCP2+cVim-4.5(2.6–7.8)6.2(2.4–16.1)
CCP2+cEnolase+20.6(7.9–54.1)40.0(11.8–135.2)
CCP2+cEnolase-5.4(3.2–9.1)10.1(4.2–24.2)
CCP2+cMBP+11.7(6.4–21.5)23.3(9.3–58.3)
CCP2+cMBP-4.1(2.2–7.7)6.7(2.3–19.0)
CCP2+cFib+8.4(4.8–14.7)17.6(7.3–42.7)
CCP2+cFib-6.0(3.0–12.0)9.2(3.1–27.2)
CCP2+cVim+cEnolase+73.1(9.8–544.8)160.0(18.6–1373.0)
CCP2+cVim-cEnolase-3.9(2.2–7.1)5.5(1.9–15.3)

Conclusion:

The gene-environment interaction between the HLA SE alleles and smoking is not specific for citrullinated a-enolase or citrullinated vimentin, but rather extends to other citrullinated antigens as well. These findings indicate that gene-environment interactions play an important role in shaping the reactivity of the ACPA response by broadening the ACPA-recognition profile.

To cite this abstract, please use the following information:
Willemze, Annemiek, Woude, Diane van der, Alemayehu, Wendim Ghidey, de Vries, René R. P, Huizinga, Tom W. J., Trouw, Leendert A., et al; The Gene-Environment Interaction between HLA-SE and Smoking Plays an Important Role in Shaping the Reactivity of the ACPA Response to Several Citrullinated Antigens. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2114
DOI: 10.1002/art.29878

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