Session Information
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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