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FRI0504 TNF-Alpha Gene Polymorphisms and Juvenile Idiopathic Arthritis: Influence on Disease Outcome and Therapeutic Response
  1. A. Scardapane1,
  2. R. Ferrante2,
  3. M. Nozzi1,
  4. V. Marzetti1,
  5. M. Lucantoni1,
  6. M. Marsili1,
  7. L. Stuppia2,
  8. F. Chiarelli1,
  9. L. Breda1
  1. 1Department of Pediatrics, Univeristy of Chieti
  2. 2Department of Genetics, University of Chieti, Chieti, Italy

Abstract

Background One of the most important molecules involved in juvenile idiopathic arthritis (JIA) is the Tumor Necrosis Factor-α (TNF-α), since several studies have demonstrated increased TNF-α levels in both serum and synovial fluid of children with chronic arthritis. Moreover, the proven efficiency of anti TNF-α biologic drugs in JIA patients suggests a key role for this cytokine.

Several single nucleotide polymorphisms (SNPs) have been identified within the promoter, exonic, intronic, and 3'untranslated region of the TNF-α gene, but conflicting results about the role of these variants in JIA have been reported and only a very small minority of these genetic variants have proven to be correlated with disease phenotype and/or clinical outcome.

Objectives To investigate the genetic contribution of TNF-α gene polymorphisms on the disease course and therapeutic response in patients with JIA.

Methods 74 Caucasian patients with JIA were recruited with a control group of 77 healthy children. DNA was extracted for analysis of TNF-α gene promoter polymorphisms at position -163, -244, -238, -376 and -308.

Results No SNPs at position -163 were observed while we observed only SNPs at position -244 and -376 in the controls. No differences were observed in the prevalence of SNPs at -238 and -308 between JIA and controls. In JIA patients no significant differences were observed between the -238 and -308 G/A genotypes and different disease phenotypes. We observed a significant lower disease activity expressed in the carriers of -308 GG genotype with respect to GA and AA genotypes after 6 (p=0.008 p=0.013 respectively) and 12 months of disease (p=0.02 p=0.08 respectively). Also the -238 GG genotypes showed a better disease course after12 months of disease. Moreover the -238/-308 GG genotypes presented the higher reduction of disease activity both after 6 (p<0.01 vs GA and p<0.01 vs AA) and 12months from baseline (p<0.01 vs GA and p<0.01 vs AA). After 12 months of biologic therapy, a significant higher disease activity was observed in patients with genotype -308AA respect to both GA (p=0.012) and GG (p=0.016).

Conclusions JIA patients carrying the TNF-α -308 GA/AA and -238 GA genotypes are associated with a worse prognosis and with a lower response to anti-TNF-α drugs.

References

  1. Field M. Tumour necrosis factor polymorphisms in rheumatic diseases. QJM 2001;94(5):237-46.

  2. Hajeer AH, Hutchinson IV. TNF-alpha gene polymorphism: clinical and biological implications. Microsc Res Tech 2000;50(3):216-28.

Disclosure of Interest None declared

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