Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Patients with rheumatoid arthritis (RA) have accelerated atherosclerosis. However, this association is not fully explained by traditional cardiovascular risk factors or markers of inflammation. Little is known about the association between genetic variation and atherosclerosis in this population. Therefore, we examined the hypothesis that in patients with RA selected candidate gene variants were associated with the presence of coronary atherosclerosis.
Methods: One hundred and forty patients with RA, enrolled in an ongoing study to evaluate the prevalence and risk factors of coronary atherosclerosis in RA, were studied. Patients fulfilled the 1987 American College of Rheumatology classification criteria for RA and were 18 years or older. Coronary artery calcium (CAC), a non-invasive measurement of coronary atherosclerosis, was measured by electron beam computed tomography. Genotyping was performed using the Illumina Goldengate platform on a custom panel of 714 single-nucleotide polymorphisms (SNPs) tagging 176 selected candidate genes. Candidate genes were chosen for relevance to autoimmune and cardiovascular risk. The association between the presence of CAC and the allele frequency of the SNP was assessed by logistic regression models, adjusted for age, sex, and race. To adjust for multiple comparisons, a false discovery rate (FDR) threshold was set at 20%.
Results: Patients with RA were 54±11 years old and predominantly Caucasian (89%) and female (69%). The presence of CAC was detected in 70 patients (50%). After adjustment for age, race, and sex, SNPs in tumor necrosis factor receptor superfamily member 11 b (TNFRSF11B), matrix metalloproteinase-3 (MMP3), interleukin-12 (IL12), matrix metalloproteinase-9 (MMP9), nucleotide-binding oligomerization domain-2 (NOD2), C-reactive protein (CRP), myeloperoxidase (MPO), resistin (RETN), interferon regulatory factor (IRF) and Fcɣ receptor 2A (FCGR2A) were associated with the presence of CAC (Table). The variant rs2073618, which encodes an Asp3Lys missense change in the osteoprotegerin gene (OPG, TNFRSF11B), was significantly associated with CAC (OR= 4.09, p=0.00026) after FDR correction.
Table: Genetic Association with Coronary Atherosclerosis in Patients with RA
|
SNP |
Gene |
Major, minor allele |
Minor allele frequency |
Odds ratio* (95% CI) |
p-value |
|
rs2073618 |
TNFRSF11B |
G,C |
0.36 |
4.09 (1.93-8.70) |
<0.001 |
|
rs522616 |
MMP3 |
T,C |
0.29 |
4.43 (1.77-11.10) |
0.001 |
|
rs2853694 |
IL12B |
T,C |
0.29 |
3.09 (1.53-6.24) |
0.002 |
|
rs3918249 |
MMP9 |
T,C |
0.49 |
0.36 (0.18-0.69) |
0.002 |
|
rs17576 |
MMP9 |
A,G |
0.45 |
0.34 (0.17-0.68) |
0.002 |
|
rs3918253 |
MMP9 |
C,T |
0.28 |
0.38 (0.20-0.72) |
0.003 |
|
rs2274756 |
MMP9 |
G,A |
0.16 |
0.24 (0.09-0.64) |
0.004 |
|
rs751271 |
NOD2 |
T,G |
0.49 |
2.57 (1.33-4.96) |
0.005 |
|
rs650108 |
MMP3 |
G,A |
0.41 |
2.82 (1.29-6.17) |
0.009 |
|
rs1800947 |
CRP |
C,G |
0.04 |
5.93 (1.43-24.71) |
0.014 |
|
rs9562414 |
TNFSF11 |
A,G |
0.06 |
0.25 (0.08-0.79) |
0.019 |
|
rs2107545 |
MPO |
T,C |
0.26 |
0.42 (0.20-0.89) |
0.023 |
|
rs3745367 |
RETN |
G,A |
0.39 |
0.45 (0.22-0.91) |
0.026 |
|
rs10954213 |
IRF5 |
G,A |
0.47 |
0.50 (0.27-0.94) |
0.030 |
|
rs633137 |
TNFSF11 |
T,A |
0.08 |
0.34 (0.13-0.91) |
0.031 |
|
rs2243828 |
MPO |
A,G |
0.23 |
0.43 (0.20-0.96) |
0.040 |
|
rs1801274 |
FCGR2A |
A,G |
0.43 |
0.52 (0.28-1.00) |
0.049 |
* Odds ratios for the comparison between minor and major allele.
Conclusion: Our results suggest that a potential functionally polymorphism of the TNFRSF11B gene, which encodes osteoprotegerin, is associated with the presence of coronary atherosclerosis in patients with RA. Replication of this finding in independent validation cohorts will be of interest.
Disclosure:
C. P. Chung,
None;
J. F. Solus,
None;
A. M. Oeser,
None;
C. Li,
None;
P. Raggi,
None;
J. R. Smith,
None;
C. M. Stein,
None.
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