Brief Report: Susceptibility to Childhood‐Onset Rheumatoid Arthritis: Investigation of a Weighted Genetic Risk Score That Integrates Cumulative Effects of Variants at Five Genetic Loci

Abstract

Objectives Children with rheumatoid-factor or anti-citrullinated peptide antibody positive juvenile idiopathic arthritis represent the childhood onset of RA (CORA). To test the hypothesis that adult-onset RA-associated variants are also associated with CORA, we investigated RA-associated variants at five loci in our CORA cohort. We also assessed the cumulative association of these variants in the susceptibility to CORA using a weighted genetic risk score (wGRS). Methods 155 children with CORA and 684 healthy controls were genotyped for five variants in PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with CORA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios for the alleles investigated, and used logistic regression to test the wGRS for association with CORA. Results CORA was associated with TNFAIP3-rs10499194 [OR 0.60 (95%CI 0.44–0.83)], PTPN22-rs2476601 [OR 1.61 (1.11–2.31)], and STAT4-rs7574865 [OR 1.41 (1.06–1.87)] variants. The wGRS was significantly different between cases and controls (P<2×10−16). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to the baseline. Higher wGRS associated with increased risk of CORA, especially among males. Conclusions TNFAIP3, STAT4 and PTPN22 variants are associated with CORA in a similar magnitude and direction as in RA, suggesting that adult-onset RA and CORA share common genetic risk factors. Utilizing a wGRS, we have demonstrated the cumulative association of RA-associated variants in the susceptibility to CORA.

Immunogenetics of juvenile idiopathic arthritis: A comprehensive review

“…Polyarticular RF-positive JIA was associated with TNFAIP3 rs10499194 (OR: 0.60 (0.44–0.83)), PTPN22 rs 2476601 (1.61 (1.11–2.31)), and STAT4 rs7574865 (OR 1.41 (1.06–1.87)) variants. It was notable that the association between TNFAIP3 rs10499194 and polyarticular RF-positive JIA in this study [76] was more pronounced than with adult RA, as the confidence intervals of the odds ratios did not overlap with those of a meta-analysis of RA [77]. Using the largest cohort of patients with polyarticular RF-positive JIA, this study demonstrated that TNFAIP3, STAT4 and PTPN22 variants were associated with RF-positive JIA in a similar magnitude and direction as had been observed in adult RA.…”

“…In a study of 155 children with polyarticular RF-positive JIA and 684 healthy autoimmunity free controls, subjects were genotyped for 5 variants in the PTPN22, TRAF1/C5, STAT4 and TNFAIP3 loci, all of which have been associated with RA [76]. Polyarticular RF-positive JIA was associated with TNFAIP3 rs10499194 (OR: 0.60 (0.44–0.83)), PTPN22 rs 2476601 (1.61 (1.11–2.31)), and STAT4 rs7574865 (OR 1.41 (1.06–1.87)) variants.…”

“…Using HLA-DRB1 and PTPN22, TRAF1/C5, STAT4 and TNFAIP3 genotypes in 149 cases with polyarticular RF-positive JIA and 373 healthy controls, a wGRS was computed for each subject [76]. Weights were based on natural log of the published OR for each allele investigated.…”

Cumulative Effects of Variants Identified by Genome-wide Association Studies in IgA Nephropathy

“…Therefore, based on data from GWASs, we constructed both weighted and unweighted genetic scores242526. We aimed to firstly construct models that were easy to interpret but were valid for risk prediction.…”

Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: A systematic review and meta-analysis

“…Polymorphisms within HLA and many other genes were evaluated for RA risk susceptibility, but had not been investigated intensively in children. To provide evidence that RA risk alleles would also be connected to CORA, Prahalad et al [81] examined RA SNPs in large set of children with CORA. CORA was most frequent among children of 11 years, and 85% of studied cases were females.…”