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A7.10 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
  1. A Krabben1,
  2. AG Wilson2,
  3. DPC de Rooy1,
  4. A Zhernakova1,3,
  5. E Brouwer4,
  6. E Lindqvist5,
  7. T Saxne5,
  8. G Stoeken1,
  9. JAB van Nies1,
  10. R Knevel1,
  11. TWJ Huizinga1,
  12. B Koeleman6,
  13. R Toes1,
  14. PK Gregersen7,
  15. AHM van der Helm-van Mil1
  1. 1Department of Rheumatology, Leiden University Medical Center, The Netherlands
  2. 2Department of Musculoskeletal Sciences, University of Sheffield, Sheffield, UK
  3. 3Genetics Department, University of Groningen, University Medical Center, Groningen, The Netherlands
  4. 4Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center, Groningen, The Netherlands
  5. 5Department of Rheumatology, Lund University, Skåne University Hospital, Lund, Sweden
  6. 6Department of Medical Genetics, Complex Genetics Section, Utrecht, The Netherlands
  7. 7Feinstein Institute for Medical Research and North Shore–Long Island Jewish Health System, Manhasset, New York, USA

Abstract

Objective The progression of joint destruction in rheumatoid arthritis (RA) is determined by genetic factors. Changes in IL-4 and IL-4R genes have been associated with RA severity but not replicated. We studied the association between IL-4 and IL-4R tagging SNPs and progression rate of joint damage in RA 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 3,415 X-rays of 1,953 RA-patients; these included data-sets from Groningen (NL), Lund (SE), Sheffield (UK), NARAC (USA), Wichita (USA) and NDB (USA). The relative increase in progression rate per year in the presence of a genotype was determined in each cohort. An inverse variance weighting meta-analysis was done on the six datasets 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 = 0.02 and Rs1119132, p = 0.001).

Conclusions Genetic variants in IL-4R were identified and independently replicated to associate with progression rate of joint damage in RA.

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