Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Rheumatoid arthritis (RA) is a common autoimmune disease that is associated with a progressive loss of the joints induced by a chronic inflammation of the joint synovium. The production of anti-citrullinated peptide/protein antibodies (ACPA) is a common but not essential characteristic of RA patients, which is thought to be influenced by the genetic background. To date, the genetic background of ACPA negative patients (ACPA-) remains widely unknown. Therefore, our goal was to analyze the genetic risk factors that contribute to ACPA- RA.
Methods: We performed a large scale genome wide association study in three European cohorts comprising 1,148 ACPA- RA patients and 6,008 controls. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1,922 ACPA- RA patients and 7,087 controls). The HLA region underwent a specific imputation process which inferred the classical HLA alleles, polymorphic amino acid positions and SNPs. Finally, we recursively searched for models which better explained the association in the HLA region following a step-wise strategy.
Results: The combined analysis of the three cohorts identified a peak of association in the HLA-region and 34 non-HLA loci showed suggestive associations. These signals were selected for follow-up using meta-analysis with a previous report. The meta-analysis confirmed the association of the HLA region, a suggestive association in the CLYBL locus (rs9557321, p = 5.82×10-8) and two tier 2 associations (rs518167 in GRM5; rs3790022 in the RNASEH2B-FAM124A region). In addition, we observed nominal associations in previously known susceptibility loci. In the case of the TNPO3–IRF5 region, rs12531711 showed a remarkable risk association with ACPA- RA in the combined analysis (p = 4.35×10-5).
After the imputation in the HLA region, the most significant association corresponded to the HLA-DRB1 Leu67 variant (p-value = 9.41×10-10). Furthermore, we identified two additional independent amino acid signals: HLA-B Asp9 and HLA-DRB1 Thr181. Finally, we confirmed that the model including all the previously mentioned amino acid variants was the most parsimonious explanation and accounted for the observed genome-wide associations in this region.
Conclusion: The present report analyzed the genetic component of a large cohort of ACPA- RA patients compared to non-affected controls following a genome-wide strategy. Our results replicated previous findings in different loci and revealed a novel suggestive susceptibility factor, CLYBL. Moreover, we provided a deep insight into the influence of the HLA region in ACPA- RA. This study supported the existence of an ACPA- specific genetic component and highlighted the importance of comprehensive genetic analysis of large ACPA- RA cohorts.
Disclosure:
L. Bossini-Castillo,
None;
C. de Kovel,
None;
H. Kallberg,
None;
M. J. H. Coenen,
None;
P. P. Tak,
None;
M. D. Posthumus,
None;
C. Wijmenga,
None;
T. W. J. Huizinga,
None;
A. H. M. van der Helm-van Mil,
None;
L. Rodriguez-Rodriguez,
None;
I. Gonzalez-Alvaro,
None;
M. A. Gonzalez-Gay,
None;
I. E. van der Horst-Bruinsma,
None;
B. A. C. Dijkmans,
None;
G. J. Wolbink,
None;
R. A. Ophoff,
None;
P. L. C. M. van Riel,
None;
L. Klareskog,
None;
J. B. A. Crusius,
None;
E. Brouwer,
None;
J. Martin,
None;
N. de Vries,
None;
R. E. M. Toes,
None;
L. Padyukov,
None;
B. P. C. Koeleman,
None.
« Back to 2013 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-genome-wide-association-study-of-rheumatoid-arthritis-without-antibodies-against-citrullinated-peptides/