Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
M-ficolin is a pattern recognition molecule that collaborates with associated serine proteases as an activator of the complement system. High M-ficolin levels are strongly associated with high disease activity in early RA and low levels at baseline are strong predictors of both remission and low disease activity after one year(1). Single nucleotide polymorphisms (SNPs) in the M-ficolin gene FCN1 have been shown to influence the concentration and function of M-ficolin(2) and are associated with outcome in patients with systemic inflammation. We have now investigated associations of 7 FCN1 SNPs with DAS28, modified Total Sharp Score (mTSS), low disease activity (LDA, DAS28<3.2), and remission (DAS28≤2.6) in a cohort of 180 early RA patients.
Methods:
180 DMARD naïve RA patients with disease duration <6 months were included in a randomized double blind placebo-controlled trial (OPERA-study,NCT00660647) of methotrexate, intra-articular glucucorticoids plus either adalimumab or placebo. SNPs were analyzed with TaqMan OpenArray system (2). The associations between SNPs and endpoints were evaluated using linear or logistic regression analysis adjusted for age, sex, anti-CCP and treatment with the common allele homozygous genotype selected as reference.
Results:
Baseline characteristics were similar in the two groups, Table 1. Table 2 states the four SNPs of which the minor allele was previously shown to be associated with higher plasma M-ficolin levels in healthy adults(2). Homozygosity of the minor allele in any of these 4 SNPs was associated with higher DAS28 at both baseline (p<0.005) and after one year of aggressive treatment (p<0.009), while no effect was observed in the heterozygote state. Homozygosity of the minor allele in the 4 SNPs was further associated with increased mTSS at both baseline (p<0.02) and at year one (p<0.04), except for rs7657015 (p=0.06). The four SNPs were, in multivariate logistic regression analyses, the only variables able to predict LDA at year one (OR between 0.16 to 0.18) and the strongest predictors of remission (OR between 0.24 to 0.26) followed by treatment with adalimumab (OR between 2.49 to 2.66).
Conclusion:
Homozygosity of the minor allele of 4 FCN1 SNPs is associated with higher DAS28 levels and modified Total Sharp Score in early RA. The four SNPs were the only variables capable of predicting LDA and the strongest predictors of DAS28 remission. These data consolidate our previous findings that M-ficolin, a molecule of the innate immune system, is a strong prognostic marker at both the protein and gene level.
(1)Arthritis Rheum.2013 Dec;65(12):3045-50
(2)PLoS One.2012;7(11):e50585
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Table 1. Patient characteristics
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OPERA
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OPERA
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P value
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Placebo treated group (n=91)
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Adalimumab treated group (p=89)
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Baseline characteristics
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Female sex |
69% |
63% |
0.46 |
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Age, years |
54 (28-77) |
56 (26-78) |
0.71 |
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Disease duration, days |
83 (42-150) |
88 (42-162) |
0.74 |
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Anti-CCP positive |
70% |
60% |
0.17 |
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IgM-RF positive |
74% |
70% |
0.67 |
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DAS28 |
5.6 (3.8-7.3) |
5.5 (3.8-7.8) |
0.53 |
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C-reactive protein, mg/l |
15 (7-109) |
15 (7-133) |
0.54 |
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Tender joint count(28) |
11 (3-24) |
10 (3-27) |
0.78 |
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Swollen joint count(28) |
8 (2-22) |
8 (2-26) |
0.66 |
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VAS-patient global, mm |
65 (17-96) |
70 (12-100) |
0.27 |
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X-ray erosions (ES≥1) |
52% |
54% |
0.94 |
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Disease activity, 1 year
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DAS28 |
2.6 (1.7-4.7) |
2.0 (1.7-5.2) |
0.009 |
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DAS28 < 3.2 |
76% |
80% |
0.65 |
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DAS28 ≤ 2.6 |
49% |
74% |
<0.001 |
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C-reactive protein, mg/l |
7 (7-44) |
7 (7-21) |
0.21 |
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Values are medians with 5-95% percentile values in parentheses, unless otherwise stated. Anti-CCP = anti-cyclic citrullinated peptide, RF = rheumatoid factor, DAS28 = disease activity score 28 joints, VAS = visual analogue scale, ES = Sharp/van der Heijde Erosion Score. |
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Table 2. Linear regression analyses of the FCN1 genotype effect on the DAS28 and modified Total Sharp Score and logistic regression analyses with DAS28<3.2 and DAS28≤2.6 as endpoints.
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DAS28 – baseline
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DAS28 – year one
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mTSS – baseline
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mTSS – year one
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DAS28<3.2 at year one
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DAS28≤2.6 at year one
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rs-number
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Geno– type
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%
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β
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P value
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β
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P value
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β
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P value
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β
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P value
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OR ( CI)
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P value
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OR (CI)
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P value
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rs2989727
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T T
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36 |
ref. |
ref. |
ref. |
ref. |
ref. |
ref. |
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T C |
47 |
-0.32 |
0.08 |
-0.20 |
0.16 |
-2.05
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0.04
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-2.27
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0.03
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2.01 (0.82-4.93)
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0.13 |
1.91 (0.88-4.19) |
0.10 |
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C C
|
17 |
-0.09 |
0.70 |
0.07 |
0.71 |
-3.05
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0.02
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-3.74
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0.008
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1.39 (0.43-4.47) |
0.58 |
1.11 (0.41-3.01) |
0.83 |
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rs7857015 *
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A A
|
49 |
ref. |
ref. |
ref. |
ref. |
ref. |
ref. |
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A G |
39 |
0.06 |
0.73 |
0.10 |
0.44 |
0.67 |
0.49 |
0.40 |
0.70 |
0.85 (0.33-2.18) |
0.73 |
0.47 (0.22-1.01) |
0.06 |
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G G
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12 |
0.79
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0.002
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0.54
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0.009
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3.34
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0.02
|
2.91 |
0.06 |
0.18 (0.06-0.55)
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0.003
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0.26 (0.09-0.78)
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0.02
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rs28909068
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T T
|
81 |
ref. |
ref. |
ref. |
ref. |
ref. |
ref. |
||||||
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T C |
19 |
-0.07 |
0.73 |
-0.02 |
0.89 |
-0.59 |
0.60 |
-0.44 |
0.72 |
1.50 (0.47-4.73) |
0.49 |
1.47 (0.57-3.80) |
0.43 |
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rs10120023 *
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C C
|
49 |
ref. |
ref. |
ref. |
ref. |
ref. |
ref. |
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C T |
39 |
0.10 |
0.57 |
0.11 |
0.40 |
0.72 |
0.45 |
0.48 |
0.64 |
0.83 (0.32-2.15) |
0.71 |
0.46 (0.21-0.99)
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0.05
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T T
|
12 |
0.77
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0.004
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0.57
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0.007
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3.64
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0.01
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3.21
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0.04
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0.16 (0.05-0.52)
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0.002
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0.24 (0.08-0.75)
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0.01
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rs28909976
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del del
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35 |
ref. |
ref. |
ref. |
ref. |
ref. |
ref. |
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del T |
47 |
-0.31 |
0.09 |
-0.20 |
0.17 |
-1.99
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0.05
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-2.22
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0.04
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2.09 (0.84-5.16)
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0.11 |
1.95 (0.89-4.29) |
0.10 |
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T T
|
18 |
-0.11 |
0.64 |
0.03 |
0.87 |
-3.01
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0.02
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-3.72
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0.007
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1.57 (0.49-5.02) |
0.45 |
1.27 (0.48-3.41) |
0.48 |
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rs10117466 *
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G G
|
49 |
ref. |
ref. |
ref. |
ref. |
ref. |
ref. |
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G T |
39 |
0.08 |
0.66 |
0.03 |
0.81 |
0.48 |
0.62 |
0.35 |
0.74 |
1.07 (0.41-2.76) |
0.89 |
0.55 (0.25-1.17) |
0.12 |
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T T
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12 |
0.75
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0.005
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0.57
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0.006
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3.73
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0.01
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3.23
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0.04
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0.18 (0.06-0.57)
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0.003
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0.26 (0.08-0.79)
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0.02
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rs10858293 *
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C C
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49 |
ref. |
ref. |
ref. |
ref. |
ref. |
ref. |
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C A |
39 |
0.12 |
0.48 |
0.07 |
0.59 |
0.82 |
0.39 |
0.56 |
0.58 |
1.06 (0.41-2.74) |
0.90 |
0.55 (0.26-1.17) |
0.12 |
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A A
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12 |
0.79
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0.003
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0.56
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0.008
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3.71
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0.01
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3.30
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0.04
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0.18 (0.06-0.56)
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0.003
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0.26 (0.08-0.79)
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0.02
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Both linear and logistic regression analyses are corrected for treatment (placebo/adalimumab), age, gender and anti-CCP status. mTSS=modified Total Sharp Score, ref.=reference, β=correlation coefficient, OR = Odds Ratio, * indicate that SNPs is associated with plasma M-ficolin concentration in 346 healthy adults (2) Statistic significant results are highlighted in bold |
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Disclosure:
C. G. Ammitzbøll,
None;
R. Steffensen,
None;
S. Thiel,
None;
J. C. Jensenius,
None;
K. Horslev-Petersen,
None;
T. Ellingsen,
None;
M. L. Hetland,
None;
P. Junker,
None;
M. Ostergaard,
Abbott/Abbvie, Centocor, Merck, Schering-Plough,,
2,
Abbott/Abbvie, BMS, Boehringer-Ingelheim, Eli-Lilly, Centocor, GSK, Janssen, Merck, Mundipharma, Novo, Pfizer, Schering-Plough, Roche UCB, and Wyeth.,
5,
None,
1,
none,
3;
K. Stengaard-Pedersen,
None.
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