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Abstract Number: 2654

Genome-Wide Association Study of Methotrexate Response Identifies Novel Genes in a Large Cohort of European Juvenile Idiopathic Arthritis Cases

Joanna Cobb1, Erika Cule2, Halima Moncrieffe3, Edward Flynn4, Anne Hinks1, Fiona Patrick3, Laura Kassoumeri3, Simona Ursu5, Maja Bulatovic6, Marek Bohm7, Bertrand D. van Zelst8, Pavla Dolezalova9, Robert De Jonge8, Nico M. Wulffraat6, Stanton Newman10, Maria de Iorio11, Lucy R. Wedderburn3 and Wendy Thomson1, 1Arthritis Research UK Epidemiology Unit, Manchester Academic Health Sciences Centre, Institute of Inflammation and Repair, The University of Manchester, Manchester, United Kingdom, 2Department of Epidemiology and Biostatistics, Imperial College London, United Kingdom, 3Institute of Child Health, University College London, London, United Kingdom, 4Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academy of Health Sciences, Manchester, United Kingdom, 5Rheumatology Unit, Arthritis Research UK Centre for Adolescent Rheumatology at University College London, Great Ormond Street Hospital and UCLH, University College London, London, United Kingdom, 6Paediatric Immunology, University Medical Centre Utrecht, Utrecht, Netherlands, 7First Faculty of Medicine and General Faculty Hospital, Prague, Czech Republic, 8Clinical Chemistry, Erasmus Medical Center, Rotterdam, Netherlands, 9Pediatric Rheumatology Unit, Department of Pediatrics and Adolescent Medicine, General University Hospital in Prague, Prague, Czech Republic, 10School of Community & Health Sciences, City University London, London, United Kingdom, 11Department of Statistical Sciences, University College London, London, United Kingdom

Meeting: ACR/ARHP Annual Meeting 2012

Keywords: ,

Session Information

Title: Pediatric Rheumatology - Pathogenesis and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: The drug methotrexate (MTX) is the first line treatment for many children with Juvenile Idiopathic Arthritis (JIA). Only 45% of children treated with MTX for arthritis achieve 70% improvement as defined using internationally agreed JIA core set criteria, and a proportion of children will not respond at all to MTX treatment. Currently there are no reliable predictors to identify children likely to fail to respond. In order to identify these children early, and thus target their treatment during the apparent short window of opportunity in which disease can readily be brought into remission, the Childhood Arthritis Response to Medication Study (CHARMS) was established. Growing evidence suggests that multiple genes contribute to the genetic component of treatment response in arthritis. With this in mind, and using the CHARMS cohort, this study aimed to perform a genome wide association study (GWAS) to identify genomic loci associated with response to MTX in JIA.

Methods: Genotyping of the Illumina OmniExpress Beadchip was performed in a large cohort of 792 JIA cases from the UK, Netherlands and Czech Republic. Single nucleotide polymorphisms (SNPs) failed QC based on a call rate <98% and/or cluster separation score <0.4. Samples failed QC based on a call rate <98%, in addition outliers of mean heterozygosity, related individuals and ancestral outliers (identified using principal components analysis) were removed. The final sample size after QC was 694 cases. The 6 core outcome variables (active/limited joint counts, ESR, CHAQ, parent/physician global assessments) were collected at baseline and 6 months. MTX response was defined using the internationally developed ACR-Pedi categories (non-responder, ACR-Pedi 30, 50, 70), as well as change in each of the core outcome variables individually. Analysis was performed using ordinal and linear regressions in R vers2.15 and PLINK vers1.07. Within the most highly associated regions, IMPUTE2 was used to increase genetic coverage.

Results: A total of 587,822 SNPs (all MAF ≥5%) across the entire genome were analyzed for each of the 6 core outcome variables as well as ACR-Pedi. 16 regions containing one or more SNPs with association with MTX response at P<1x10-4 in more than one of the 7 analyses met criteria for further investigation including SNP imputation. The most highly associated SNPs were found near the genes CACNA1I, PVT1 and CFTR. These findings are currently being validated within a US cohort of JIA cases with MTX response data available in the form of active and limited joint counts.

Conclusion: These results suggest a role for novel pathways in MTX response. Further investigations within associated regions to dissect the genetic basis of MTX response will move us towards our ultimate goal of prediction of response to MTX for children with JIA.

Acknowledgements: Childhood Arthritis Prospective Study (CAPS) and Sparks-Childhood Arthritis Response to Medication Study (Sparks-CHARMS) groups. The study was funded by SPARKS UK and Arthritis Research UK.

Disclosure:

J. Cobb,
None;

E. Cule,
None;

H. Moncrieffe,
None;

E. Flynn,
None;

A. Hinks,
None;

F. Patrick,
None;

L. Kassoumeri,
None;

S. Ursu,
None;

M. Bulatovic,
None;

M. Bohm,
None;

B. D. van Zelst,
None;

P. Dolezalova,
None;

R. De Jonge,

Dutch Arthritis Association,

2;

N. M. Wulffraat,
None;

S. Newman,
None;

M. de Iorio,
None;

L. R. Wedderburn,
None;

W. Thomson,
None.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-study-of-methotrexate-response-identifies-novel-genes-in-a-large-cohort-of-european-juvenile-idiopathic-arthritis-cases/