Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Single nucleotide polymorphisms (SNPs) in the CRP gene are implicated in the regulation of the basal C-reactive protein (CRP) expression and its response to pro-inflammatory stimuli. Previous reports suggest these effects may have an impact on clinical decision-making based on CRP, e.g. DAS28 (1). We aimed to investigate for the first time the possible association between 7 SNPs in the CRP and the serum level of CRP/ DAS28 in a cohort of 180 untreated inflammatory active 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, intraarticular glucucorticoids + either adalimumab or placebo. SNPs were analyzed by the TaqMan OpenArray system. The 7 SNPs (Table 2) were selected based on previously reported effects on CRP levels(1). CRP was measured using CRP QUICK-READ (range 8–160 mg/l). The associations between SNPs (and haplotypes of SNPs) and CRP and DAS28 levels were evaluated using linear regression analysis adjusted for age, sex and treatment. For the analysis of genotypic and haplotypic effects, the common allele homozygous genotype/haplotype was selected as reference, and the effects are presented as percentage. ‘Haplo.stats’ package for R was used.
Results:
Baseline characteristics were similar in the two groups, Table 1. There were no significant genotypic or haplotypic effects of the 7 SNPs on CRP levels at baseline or one year (P≥0.080). Homozygosity for the minor allele of rs2808632 reduced borderline significant the baseline DAS28 levels to 54% P=0.055, and heterozygosity for rs1800947 increased DAS28 levels at one year to 158% P=0.03. Six haplotypes were constructed encompassing 94% of the cohort, Table 3. The H4 haplotype reduced baseline DAS28 score to 51% P=0.009, and the H6 haplotype increased the DAS28 score at one year to 168% P=0.02. No further haplotypic effect on DAS28 were observed at baseline or one year.
Conclusion:
Seven selected CRP gene SNPs had no impact on pre- and one year post-treatment levels of CRP. Minor genotypic and haplotypic effects on DAS28 scores were observed, but these were not consistent between baseline and one year. This study shows that DAS28 can be used for clinical decision-making without adjustment for CRP gene variants.
(1)Nat Rev Rheum 2011;7(5):282-9.
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Table 1. Patient characteristics
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OPERA
|
OPERA
|
P value
|
|
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Placebo treated group (n=91)
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Adalimumab treated group (p=89)
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|
|
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Patient characteristics
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Female sex |
69% |
63% |
0.46 |
|
Age, years |
54 (28-77) |
56 (26-78) |
0.71 |
|
Disease duration, days |
83 (42-150) |
88 (42-162) |
0.74 |
|
Anti-CCP positive |
70% |
60% |
0.17 |
|
IgM-RF positive |
74% |
70% |
0.67 |
|
DAS28 |
5.6 (3.8-7.3) |
5.5 (3.8-7.8) |
0.53 |
|
C-reactive protein, mg/l |
15 (7-109) |
15 (7-133) |
0.54 |
|
Tender joint count(28) |
11 (3-24) |
10 (3-27) |
0.78 |
|
Swollen joint count(28) |
8 (2-22) |
8 (2-26) |
0.66 |
|
VAS-patient global, mm |
65 (17-96) |
70 (12-100) |
0.27 |
|
Baseline 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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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 genotype effect on the mean CRP and DAS28 levels relative to the major genotype.
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CRP levels relative to major genotype in %
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DAS28 levels relative to major genotype in %
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Rs-number
|
Genotype
|
%
|
Baseline
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P value
|
Year one
|
P value
|
Baseline
|
P value
|
Year one
|
P value
|
|
rs11265257
|
C C
|
38 |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
|
C T |
46 |
103 (75-141) |
P = 0.87
|
99 (85-115)
|
P = 0.88
|
95 (67-136)
|
P = 0.78
|
99 (75-130)
|
P = 0.92
|
|
|
T T
|
16 |
79 (51-122)
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P = 0.29 |
105 (85-129) |
P = 0.68
|
85 (52-139)
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P = 0.52 |
98 (68-141)
|
P = 0.90
|
|
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rs1130864
|
G G
|
49 |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
|
A G |
41 |
92 (67-125)
|
P = 0.58 |
97 (84-113)
|
P = 0.73
|
119 (84-167) |
P = 0.32 |
109 (84-142) |
P = 0.51 |
|
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A A
|
10 |
119 (72-199) |
P = 0.50 |
88 (69-112)
|
P = 0.30 |
117 (67-207) |
P = 0.58 |
109 (71-167) |
P = 0.71
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|
|
rs1205
|
C C
|
46 |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
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C T |
44 |
105 (77-143) |
P = 0.75
|
89 (78-101)
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P = 0.08 |
101 (71-142) |
P = 0.97
|
86 (66-113)
|
P = 0.28 |
|
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T T
|
10 |
69 (42-114)
|
P = 0.15 |
99 (81-123)
|
P = 0.96
|
103 (59-182) |
P = 0.91
|
102 (66-157) |
P = 0.93
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|
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rs1800947
|
C C
|
89 |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
|
C G |
11 |
88 (55-140)
|
P = 0.59 |
96 (75-122)
|
P = 0.73
|
127 (76-213) |
P = 0.37 |
158 (103-241) |
P = 0.03 |
|
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rs2808632
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T T
|
46 |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
|
G T |
46 |
115 (85-155) |
P = 0.37 |
97 (84-112)
|
P = 0.65
|
113 (81-158) |
P = 0.46 |
104 (81-135) |
P = 0.75
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G G
|
8
|
113 (64-200) |
P = 0.67
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117 (89-154) |
P = 0.26 |
54 (29-101)
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P = 0.06 |
99 (61-161)
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P = 0.98
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rs3093077
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A A
|
89 |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
|
A C |
11 |
94 (58-151)
|
P = 0.79
|
110 (88-137) |
P = 0.41 |
80 (47-136)
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P = 0.41 |
80 (54-118)
|
P = 0.26 |
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rs876538
|
C C
|
60 |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
100 (ref.) |
– |
|
C T |
37 |
128 (94-174) |
P = 0.12 |
101 (87-117) |
P = 0.93
|
131 (93-184) |
P = 0.12 |
111 (85-144) |
P = 0.45 |
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T T
|
3
|
124 (55-281) |
P = 0.60
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85 (56-129)
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P = 0.44 |
57 (23-140)
|
P = 0.22 |
79 (38-165)
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P = 0.53 |
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Numbers in parantheses are 95% confidence intervals. Calculated by linear regression, corrected for treatment (placebo/adalimumab), age and gender. ref.=reference |
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Table 3. Linear regression analyses of the haplotype effect on the mean CRP and DAS28 levels relative to the major haplotype.
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CRP levels relative to major genotype in %
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DAS28 levels relative to major genotype in %
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Haplotype
|
Frequency
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SNPs#
|
Baseline
|
Year one
|
Baseline
|
Year one
|
|
H1 |
30 % |
C A C C T A C
|
100 (ref.) |
100 (ref.) |
100 (ref.) |
100 (ref.) |
|
H2 |
26 % |
T G T C T A C |
93 (72-121) P = 0.58 |
93 (72-121) P = 0.58 |
91 (68-121) P = 0.51 |
83 (67-103) P = 0.10 |
|
H3 |
21 % |
C G C C G A T
|
115 (86-154) P = 0.35 |
115 (86-154) P = 0.35 |
95 (69-131) P = 0.77
|
99 (77-126) P = 0.93
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H4 |
7 % |
T G C C G A C
|
80 (51-126) P = 0.33 |
80 (51-126) P = 0.33 |
51 (31-84) P = 0.009
|
115 (80-165) P = 0.45 |
|
H5 |
5 % |
C G C C T C C
|
96 (59-156) P = 0.87
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96 (59-156) P = 0.87
|
78 (46-133) P = 0.36 |
75 (51-111) P = 0.15 |
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H6 |
5 % |
T G T G T A C |
93 (56-153) P = 0.76
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93 (56-153) P = 0.76
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115 (66-200) P = 0.62
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168 (108-261) P = 0.02 |
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(#) The 7 SNPs defining the 6 haplotypes are listed as follows (rs11265257, rs1130864, rs1205, rs1800947, rs2808632, rs3093077, rs876538). ref.=reference |
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Disclosure:
C. G. Ammitzbøll,
None;
R. Steffensen,
None;
P. Junker,
None;
M. Østergaard,
None;
J. Johansen,
None;
J. Pødenphant,
None;
M. L. Hetland,
None;
H. M. Lindegaard,
None;
T. Ellingsen,
None;
K. Stengaard-Pedersen,
None.
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