Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
The severity of RA is reflected by the severity of radiological joint destruction. It is highly variable between patients and up to 58% of this variance is explained by genetic factors. In order to increase the understanding of the processes underlying joint damage progression, it is relevant to identify individual risk factors. In vitro studies and mice studies showed that IL-4 has a role in suppressing arthritis severity. The effect of IL-4 is mediated by a heterodimeric receptor composed of the IL-4R alpha chain. Several genetic variants in IL-4 and IL-4R have been described to associate with RA severity, though these findings have not been replicated. Together these data prompted us to investigate the association between IL-4 and IL-4R tagging SNPs and progression rate of joint damage in a multi-cohort candidate gene study.
Methods:
IL-4 and IL-4R tagging SNPs (8 and 39, respectively) were genotyped in 600 RA patients of whom 2,846 sets of hands and feet X-rays were collected during 7 years follow-up. Subsequently, significantly associated SNPs were genotyped and studied in relation to 3,523 X-rays of 2,064 RA patients of several European and North-American cohorts. These concerned data-sets from Lund (Sw) (781 X-rays in 147 patients), Sheffield (UK) (391 X-rays in 391 patients), Groningen (NL) (872 X-rays in 280 patients), NARAC (USA) (385 X-rays in 385 patients), Wichita (USA) (337 X-rays in 101 patients) and NDB (USA) (757 X-rays in 757 patients). Three SNPs of phase-2 were not available for the latter two cohorts. In all cohorts X-rays were scored with high reproducibility. The relative increase in progression rate per year in the presence of a genotype was determined, as this outcome measure is comparable between cohorts. Subsequently, since the individual replication cohorts had less number of X-rays than the discovery cohort, an inverse variance weighting meta-analysis was done on the cohorts that together formed the replication phase.
Results:
In the discovery phase none of the IL-4 SNPs and seven of the IL-4R SNPs were significantly associated with joint damage progression rate. In the replication phase, two SNPs in IL-4R gene were significantly associated with joint damage progression rate (rs1805011, p=0.017 and rs1119132, p=0.001). After Bonferroni correction for testing seven SNPs in phase-2 rs1119132 remained significantly associated with joint progression rate (pcorrected=0.007). Leiden RA-patients carrying both minor alleles of rs1119132 had a 1.09 fold rate of joint destruction compared to other patients, which corresponds to 81% higher rate of joint destruction over a period of 7 years.
Conclusion: rs1119132 in IL-4R was identified as well as independently replicated to associate with progression rate of joint damage in RA.
Disclosure:
A. Krabben,
None;
A. G. Wilson,
None;
R. Knevel,
None;
A. Zhernakova,
None;
E. Brouwer,
None;
E. Lindqvist,
None;
T. Saxne,
None;
G. Stoeken-Rijsbergen,
None;
J. A. B. van Nies,
None;
D. P. C. de Rooy,
None;
T. W. J. Huizinga,
None;
B. P. C. Koeleman,
None;
R. E. M. Toes,
None;
P. K. Gregersen,
None;
A. H. M. van der Helm-van Mil,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-variants-in-the-il-4-and-il-4-receptor-genes-in-association-with-the-severity-of-joint-damage-in-rheumatoid-arthritis-a-study-in-seven-cohorts/