ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1210

Effect of HLA-DRB1*0901 Suggest Distinctive Mechanisms of Rheumatoid Arthritis Susceptibility

So-Young Bang1, Hye-Soon Lee2, Kyung Wha Lee3 and Sang-Cheol Bae4, 1Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea, 2Department of Rheumatology, Hanyang University Guri Hospital, Guri, South Korea, 3Hallym Institute for Genome Application,Hallym University Sacred Heart Hospital, Anyang, South Korea, 4Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Although HLA-DRB1 shared epitope (SE) alleles and DRB1*0901 have repeatedly been shown to be associated with RA susceptibility, the effect of each allele on levels of anti-cyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with smoking in RA remains to be fully defined. We aimed to investigate whether DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti-CCP positive or negative RA.

Methods: All RA patients (n =1,924) and controls (n = 1,119) were Korean. Odds ratios and biologic interactions as departure from additivity or multiplicity were analyzed by logistic regression.

Results: The *0901 allele significantly decreased anti-CCP levels in both the SE-negative and SE-positive group. We found a hierarchy of anti-CCP levels depending upon the combination of RA risk alleles (P=5.55×10–11). In the hierarchy, individuals carrying SE/SE had the highest (614 units/ml) and *0901/*0901 had the lowest levels (189 units/ml). The SE alleles interacted with smoking strongly in anti-CCP positive RA (AP=0.48 [0.25-0.71] and slightly in anti-CCP negative RA (AP=0.43 [0.02-0.81]). In addition, each of the SE alleles significantly interacted with smoking in anti-CCP positive RA. In anti-CCP negative RA, only *1001 interacted with smoking. However, DRB1*0901 did not interacted with smoking in both anti-CCP positive and negative RA groups. Interestingly, interactions between the two most significant risk alleles, *0405 and *0901, (AP=0.68 [0.46-0.89], multiplicity p=0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Moreover, smoking amplified the risk for RA by significant synergistic interaction with the heterozygote *0405/*0901 in anti-CCP negative RA (AP=0.80 [0.32-1.28]) but not in anti-CCP positive RA.

Conclusion: DRB1*0901 differs from SE alleles regarding to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of *0901 in RA pathogenesis, which may bypass anti-CCP formation. In addition, significant increase of *0405/*0901 heterozygote in RA susceptibility may be attributable to the synergistic contribution of two different pathways in which two alleles participate independently.

Table 1. Risk of anti-CCP positive and anti-CCP negative RA according to HLA-DRB1 and smoking

 

anti-CCP positive RA

anti-CCP negative RA

HLA-DRB1/ Smoking

No. of cases/controls

OR† (95% CI)

No. of cases/controls

OR† (95% CI)

SE

– /-

188/502

reference

58/502

reference

-/+

30/63

2.17 (1.25-3.77)

13/63

3.76 (1.74-8.15)

+/-

826/328

7.28 (5.85-9.06)

99/328

2.66 (1.87-3.79)

+/+

166/46

16.31 (9.96-26.74)

22/46

9.05 (4.43-20.37)

              AP‡

0.48 (0.25-0.71)

0.43 (0.02-0.81)

            RERI‡

7.87 (0.53-15.21)

4.08 (-2.34-10.50)

              S‡

2.06 (1.28-3.31)

1.92 (0.84-4.41)

*0901

-/-

188/502

reference

58/502

reference

-/+

30/63

2.54 (1.41-4.60)

13/63

2.90 (1.30-6.45)

+/-

292/162

4.97 (3.83-6.44)

41/162

2.19 (1.41-3.40)

+/+

47/33

7.77 (4.12-14.63)

13/33

5.66 (2.38-13.45)

AP‡

0.16 (-0.32-0.65)§

0.28 (-0.32-0.87)§

                RERI‡

1.25 (-3.21-5.72)

1.57 (-2.85-0.87)

                  S‡

1.23 (0.63-2.38)

1.51 (0.54-4.20)

Table 2. Synergistic effect of having *0405 and *0901 alleles in RA according to anti-CCP status

 

anti-CCP positive RA

anti-CCP negative RA

 

Genotype

No. of cases/controls

OR† (95% CI)

No. of cases/controls

OR† (95% CI)

non-risk / non-risk

220/574

reference

71/574

reference

*0901/ non-risk

173/151

2.94 (2.24-3.87)

31/151

1.63 (1.03-2.59)

*0405/ non-risk

359/135

7.54 (5.82-9.77)

51/135

3.11 (2.07-4.67)

*0901/*0901

29/11

6.92 (3.36-14.24)

2/11

1.44 (0.31-6.64)§

*0405/*0405

61/9

20.22 (9.77-41.82)

2/9

1.85 (0.39-8.74)§

*0405/*0901

90/10

28.03 (14.17-55.45)

16/10

13.66 (5.93-31.44)

AP‡

                       0.66 (0.43-0.89)

0.73 (0.49-0.96)

 

RERI‡

                      18.69 (-0.28-37.66)

                           9.98 (-1.23-21.20)

 

S‡

                       3.19 (1.57-6.52)

                           4.63 (1.75-12.26)

 

Multiplicity‡

                       P = 0.025

                            P = 4.32×10-4

 

† All odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by comparing each group with the corresponding reference group [individuals without SE &*0901] adjusted for age and sex.

Disclosure:

S. Y. Bang,
None;

H. S. Lee,
None;

K. W. Lee,
None;

S. C. Bae,
None.

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