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Author Notes:

Correspondence: sprahal@emory.edu

MK, MRP, AW, MRB carried out the DNA extraction and genotyping of the subjects. LP recruited participants and organized participant data. SAH, KRS, LBV, JFB recruited subjects and supervised phenotypic data collection. KAB, MPE, KNC, SLG, and LBJ participated in the analysis of data and interpretation, and helped draft the manuscript. SP conceived of the study, participated in its design and coordination, recruited participants, and helped draft the manuscript. All authors read and approved the final manuscript.

We are grateful to Dr. Stephen Guthery MD, at the University of Utah for sharing control samples and Bronte Clifford for subject enrollment.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

Supported by The National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23-AR50177, R01-AR060893), and The National Center for Research Resources (UL1-RR025764 and C06-RR11234), The Arthritis Foundation, and The Val A Browning Charitable Foundation, and The Primary Children’s Medical Center Foundation, Salt Lake City, UT, and the Marcus Foundation Inc., Atlanta, GA.

Keywords:

  • Genetics
  • Juvenile idiopathic arthritis
  • Association
  • Replication

Meta-analysis confirms association between TNFA-G238A variant and JIA, and between PTPN22-C1858T variant and oligoarticular, RF-polyarticular and RF-positive polyarticular JIA

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Journal Title:

Pediatric Rheumatology

Volume:

Volume 11

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: Although more than 100 non-HLA variants have been tested for associations with juvenile idiopathic arthritis (JIA) in candidate gene studies, only a few have been replicated. We sought to replicate reported associations of single nucleotide polymorphisms (SNPs) in the PTPN22, TNFA and MIF genes in a well-characterized cohort of children with JIA. Methods: We genotyped and analyzed 4 SNPs in 3 genes: PTPN22 C1858T (rs2476601), TNFA G-308A, G-238A (rs1800629, rs361525) and MIF G-173C (rs755622) in 647 JIA cases and 751 healthy controls. We tested for association between each variant and JIA as well as JIA subtypes. We adjusted for multiple testing using permutation procedures. We also performed a meta-analysis that combined our results with published results from JIA association studies. Results: While the PTPN22 variant showed only modest association with JIA (OR = 1.29, p = 0.0309), it demonstrated a stronger association with the RF-positive polyarticular JIA subtype (OR = 2.12, p = 0.0041). The MIF variant was not associated with the JIA as a whole or with any subtype. The TNFA-238A variant was associated with JIA as a whole (OR 0.66, p = 0.0265), and demonstrated a stronger association with oligoarticular JIA (OR 0.33, p = 0.0006) that was significant after correction for multiple testing. TNFA-308A was not associated with JIA, but was nominally associated with systemic JIA (OR = 0.33, p = 0.0089) and enthesitis-related JIA (OR = 0.40, p = 0.0144). Meta-analyses confirmed significant associations between JIA and PTPN22 (OR 1.44, p <0.0001) and TNFA-238A (OR 0.69, p < 0.0086) variants. Subtype meta-analyses of the PTPN22 variant revealed associations between RF-positive, RF-negative, and oligoarticular JIA, that remained significant after multiple hypothesis correction (p < 0.0005, p = 0.0007, and p < 0.0005, respectively). Conclusions: We have confirmed associations between JIA and PTPN22 and TNFA G-308A. By performing subtype analyses, we discovered a statistically-significant association between the TNFA-238A variant and oligoarticular JIA. Our meta-analyses confirm the associations between TNFA-238A and JIA, and show that PTPN22 C1858T is associated with JIA as well as with RF-positive, RF-negative and oligoarticular JIA.

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© 2013 Kaalla et al.; licensee BioMed Central Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 2.0 Generic License (http://creativecommons.org/licenses/by/2.0/).

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