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

Abstract

BackgroundAlthough 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.MethodsWe 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.ResultsWhile 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).ConclusionsWe 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.

CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis

“…All genes except ANKRD55 , have obvious roles in immune processes. It should be noted that the C allele of rs755622 in the promoter region of MIF (encoding the proinflammatory cytokine macrophage migration inhibitory factor) is associated with protection to JIA in our study, but this conflicts with results from other JIA cohorts that suggest association of the C allele with susceptibility 28 – 31. The reason for these opposing results is not clear, but the MAF of this SNP in our control cohort is comparable to the MAF in other northwest European control cohorts 29 32 – 34.…”

The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females

“…In addition, previously reported subtype-specific associations of JIA with rs2476601 found significant associations only in subtypes with a female bias. 16 In both the previously published data and our study, the more rare subtype samples were too small to draw any firm conclusions.…”

Blueberry Improves the Therapeutic Effect of Etanercept on Patients with Juvenile Idiopathic Arthritis: Phase III Study

“…A total of 450 males and females with JIA, under the age of 16 years, were selected if they met the criteria of ACR for RA for more than one year and were classified as Class I, II, or III (Verhoef et al 2005). The three major types of JIA are oligoarticular JIA (OJIA), polyarticular JIA (PJIA) and systemic JIA (SJIA) (Kaalla et al 2013).…”