THE ASSOCIATION OF VITAMIN D STATUS WITH DISEASE ACTIVITY IN CANADIAN CHILDREN NEWLY DIAGNOSED WITH JUVENILE IDIOPATHIC ARTHRITIS

Introduction: Juvenile Idiopathic Arthritis (JIA) is among the most common chronic diseases of childhood. The cause of JIA is unknown but is suspected to occur in genetically susceptible children with some unidentified environmental exposure. Vitamin D, through its genetic or environmental influences, may regulate inflammation and immune responses in JIA. To date, no 25 hydroxyvitamin D (25(OH)D) concentrations specific to children with JIA have been suggested.\nObjective. The overarching goal of this research was to understand how vitamin D affects disease activity in children who are suffering from JIA. The specific objectives were to: (1) Compare vitamin D status between healthy children and patients with JIA. (2) Determine vitamin D status and its association with disease activity and outcomes in children with JIA. (3) Identify potential associations of vitamin D pathway gene polymorphisms and JIA.\nMethods. Data from the Biologically-Based Outcome Predictors (BBOP) Study, a prospective multi-center study of newly diagnosed Canadian children with JIA (n=186, 2007-2012) was analyzed. Blood samples were obtained at baseline and 6 months later to measure 25(OH)D)and plasma inflammatory cytokine concentrations. Saliva was collected for genetic analysis. Vitamin D-related factors (milk intake, season of measurement, supplementation and steroid use) and clinical data to define remission were recorded every 6 months for 2 years.\nFirst, BBOP children were compared to healthy children from the Canadian Health Measures Survey (CHMS). 25(OH)D concentrations, vitamin D related factors, measures of inflammation, and anthropometric measurements were evaluated. Longitudinal analysis then explored whether 25(OH)D and related factors could predict disease activity in BBOP children. Genome-Wide Association Studies (GWAS) techniques were then applied to identify frequent gene polymorphisms of potential relevance to the vitamin D pathway in JIA. Significant variables from linear regressions, genes identified through GWAS, vitamin D pathway genes and interactions were selected for further analysis. \nResults. Mean 25(OH)D concentration was significantly higher in JIA patients (79 ± 3.1 nmol/L vs. 68 ± 1.8 nmol/L p <0.05) and JIA patients used vitamin D supplements more often (50% vs. 7% p <0.05). Children with JIA were more likely to be born in the fall and winter compared to healthy children. C-reactive protein concentration (CRP) and erythrocyte sedimentation rate (ESR) decreased significantly over the 2 years (p<0.05). Increased 25(OH)D or its associated factors predicted lower ESR, CRP and pro-inflammatory cytokine concentrations. Overall, 36% of children achieved remission on continuing medications; 25% had sustained remission after discontinuing medication. GWAS identified the following genetic components: NOTCH4, C6orf10, HLA-DQA1, LEP, IGFBP4, and GPS1. Interactions between frequent gene polymorphisms and those in the vitamin D pathway (VDR, GC, CYP24A1, and CYP1R1) significantly predicted disease activity-related outcomes. Genes, when included, modified the association between 25(OH)D and indicators of disease activity. With and without genes in the model, drinking milk every day predicted a reduction in indicators of disease activity as measured by CRP, ESR, and interleukin-6. \nConclusion. Using 25(OH)D recommendations suggested for healthy children, 25(OH)D was adequate in the JIA population. A preponderance of JIA patients born in seasons associated with reduced endogenous vitamin D could implicate low vitamin D during gestation and early life as a factor influencing JIA pathogenesis. Milk intake, as a source of dietary vitamin D, is associated with suppression of inflammation in children with JIA. This is the first time gene and environment influences in relation to vitamin D were analyzed together in association with JIA disease activity. Environmental, biochemical, and genetic factors, including their interactions, predict disease activity in children with JIA.

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