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  • Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis

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Clinical and epidemiological research
Extended report
Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis
  1. Anne Hinks1,
  2. Halima Moncrieffe2,
  3. Paul Martin1,
  4. Simona Ursu2,
  5. Sham Lal1,
  6. Laura Kassoumeri2,
  7. Tracey Weiler3,
  8. David N Glass4,
  9. Susan D Thompson4,
  10. Lucy R Wedderburn2,
  11. Wendy Thomson1
  1. 1Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
  2. 2Rheumatology Unit, UCL Institute of Child Health, London, UK
  3. 3Department of Molecular Sciences, Medical University of the Americas, Charlestown, West Indies
  4. 4Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  1. Correspondence to Dr Anne Hinks, Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK; anne.hinks{at}manchester.ac.uk

Abstract

Objectives Methotrexate (MTX) is the mainstay treatment for juvenile idiopathic arthritis (JIA), however approximately 30% of children will fail to respond to the drug. Identification of genetic predictors of response to MTX would be invaluable in developing optimal treatment strategies for JIA. Using a candidate gene approach, single nucleotide polymorphisms (SNPs) within genes in the metabolic pathway of MTX, were investigated for association with response to treatment in JIA cases.

Methods Tagging SNPs were selected across 13 MTX metabolic pathway genes and were genotyped using Sequenom genotyping technology in subjects recruited from the Sparks Childhood Arthritis Response to Medication Study. Response to MTX was defined using the American College of Rheumatology (ACR) paediatric response criteria and SNP genotype frequencies were compared between the worst and best responders (ACR-Ped70) to MTX. An independent cohort of US JIA cases was available for validation of initial findings.

Results One SNP within the inosine triphosphate pyrophosphatase gene (ITPA) and two SNPs within 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene (ATIC) were significantly associated with a poor response to MTX. One of the ATIC SNPs showed a trend towards association with MTX response in an independent cohort of US JIA cases. Meta-analysis of the two studies strengthened this association (combined p value=0.002).

Conclusions This study presents association of a SNP in the ATIC gene with response to MTX in JIA. There is now growing evidence to support a role of the ATIC gene with response to MTX treatment. These results could contribute towards a better understanding of and ability to predict MTX response in JIA.

This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl

https://doi.org/10.1136/ard.2010.146191

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    Footnotes

    • LRW and WT contributed equally to this work

    • Funding Sparks CHARMS is funded by Sparks UK and the Big Lottery Fund UK. The study is on the UK Medicines for Children Research Network (MCRN) portfolio. This work was supported by the Arthritis Research Campaign: arc grant reference no: 17552. The US cohort collection and genotyping were supported by NIH (NIAMS N01AR42272, P30AR47363 and P60AR47784).

    • Competing interests The authors have no competing interests to disclose.

    • Ethics approval This study was conducted with the approval of the Institute of Child Health/Great Ormond Street NHS Trust Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.