The plasma metabolome of juvenile idiopathic arthritis varies according to subtype and underlying inflammatory status.

Background: Juvenile idiopathic arthritis (JIA) is challenging to classify and effectively monitor due to the lack of disease- and subtype-specific biomarkers. A robust molecular signature that tracks with specific JIA features over time is urgently required, and targeted plasma metabolomics may reveal such a signature. The primary aim of this study was to characterise the differences in the plasma metabolome between JIA patients and non-JIA controls and identify specific markers of JIA subtype.

Genomic risk scores for juvenile idiopathic arthritis and its subtypes.

Objectives: Juvenile idiopathic arthritis (JIA) is an autoimmune disease and a common cause of chronic disability in children. Diagnosis of JIA is based purely on clinical symptoms, which can be variable, leading to diagnosis and treatment delays. Despite JIA having substantial heritability, the construction of genomic risk scores (GRSs) to aid or expedite diagnosis has not been assessed.

Effect of MUC1 length polymorphisms on the NLRP3 inflammasome response of human macrophages.

Mucin 1 is a cell-membrane associated mucin, expressed on epithelial and immune cells that helps protect against pathogenic infections. In humans, MUC1 is highly polymorphic, predominantly due to the presence of a variable number tandem repeat (VNTR) region in the extracellular domain that results in MUC1 molecules of typically either short or long length. A genetic link is known between these MUC1 polymorphisms and inflammation-driven diseases, although the mechanism is not fully understood.

Higher Sun Exposure is Associated With Lower Risk of Pediatric Inflammatory Bowel Disease: A Matched Case-control Study.

Objectives: The incidence of pediatric inflammatory bowel disease (IBD) is increasing worldwide. Ecological studies show higher incidence in regions at higher latitude or lower ambient ultraviolet radiation; individual-level associations with sun exposure have not been assessed.

Methods: We recruited children (0-17 years) with IBD from 2 large hospitals in Melbourne, Australia.

Extensive Ethnic Variation and Linkage Disequilibrium at the Locus: Different Genetic Associations Revealed in Kawasaki Disease.

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs.

Genetic determinants of paediatric food allergy: A systematic review.

Background: The genetic determinants of food allergy have not been systematically reviewed. We therefore systematically reviewed the literature on the genetic basis of food allergy, identifying areas for further investigation.

Methods: We searched three electronic databases (MEDLINE, EMBASE and PubMed) on 9 January 2018.

Association of Increased Sun Exposure Over the Life-course with a Reduced Risk of Juvenile Idiopathic Arthritis.

Cutaneous sun exposure is an important determinant of circulating vitamin D. Both sun exposure and vitamin D have been inversely associated with risk of autoimmune disease. In juvenile idiopathic arthritis (JIA), low circulating vitamin D appears common, but disease-related behavioral changes may have influenced sun exposure.

Ximmer: a system for improving accuracy and consistency of CNV calling from exome data.

Background: While exome and targeted next-generation DNA sequencing are primarily used for detecting single nucleotide changes and small indels, detection of copy number variants (CNVs) can provide highly valuable additional information from the data. Although there are dozens of exome CNV detection methods available, these are often difficult to use, and accuracy varies unpredictably between and within datasets.

Findings: We present Ximmer, a tool that supports an end-to-end process for evaluating, tuning, and running analysis methods for detection of CNVs in germline samples.

Children with East Asian-Born Parents Have an Increased Risk of Allergy but May Not Have More Asthma in Early Childhood.

Background: We previously reported that infants with Asian-born parents are 3 times more likely to have IgE-mediated food allergy than those with Australian-born parents. It is unknown whether this translates to the increased risk of other allergic diseases later in childhood and whether ancestry interacts with other risk factors for allergic disease development.

Objective: To compare prevalence and risk factors for allergic rhinitis, asthma, and aeroallergen sensitization at age 6 between children with East Asian-born and Caucasian-born parents.

Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry.

Complex diseases are often underpinned by multiple common genetic variants that contribute to disease susceptibility. Here, we describe a cost-effective tag single nucleotide polymorphism (SNP) approach using a multiplexed genotyping assay with mass spectrometry, to investigate gene pathway associations in clinical cohorts. We investigate the food allergy candidate locus Interleukin13 (IL13) as an example.

Higher parental occupational social contact is associated with a reduced risk of incident pediatric type 1 diabetes: Mediation through molecular enteroviral indices.

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008-2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples.

The DNA methylation landscape of CD4 T cells in oligoarticular juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is presumed to be driven by an adverse combination of genes and environment. Epigenetic processes, including DNA methylation, act as a conduit through which the environment can regulate gene activity. Altered DNA methylation has been associated with adult autoimmune rheumatic diseases such as rheumatoid arthritis, but studies are lacking for paediatric autoimmune rheumatic diseases including JIA.

Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin-Angiotensin-Aldosterone System and Blood Pressure.

Background: Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis).

Methods And Results: We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (), angiotensinogen (), angiotensin-converting enzyme (), angiotensin II type 1 receptor (), and aldosterone synthase (), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models.

Conjunctival Ultraviolet Autofluorescence as a Measure of Past Sun Exposure in Children.

Conjunctival ultraviolet autofluorescence (CUVAF) area detected from UVAF photographs is a recently developed potential marker for past sun exposure, but its relationship with sun-related factors has not been fully investigated. The study included 339 healthy children ages 5 to 15 years in Melbourne, Australia. Data were collected by questionnaire and examination at school.

A survey of national and multi-national registries and cohort studies in juvenile idiopathic arthritis: challenges and opportunities.

Background: To characterize the existing national and multi-national registries and cohort studies in juvenile idiopathic arthritis (JIA) and identify differences as well as areas of potential future collaboration.

Methods: We surveyed investigators from North America, Europe, and Australia about existing JIA cohort studies and registries. We excluded cross-sectional studies.

Environmental and genetic determinants of two vitamin D metabolites in healthy Australian children.

Background: Vitamin D deficiency has been associated with adverse health outcomes. We examined genetic and environmental determinants of serum 25(OH)D3 and 1,25(OH)2D3 in childhood.

Methods: The study sample consisted of 322 healthy Australian children (predominantly Caucasians) who provided a venous blood sample.

The MassARRAY System for Targeted SNP Genotyping.

Research to understand the genetic basis of disease, particularly complex disease, regularly involves single nucleotide polymorphism (SNP) genotyping. The use of genome-wide SNP genotyping arrays has become increasingly more commonplace for gene discovery. However, smaller-scale genotyping platforms capable of efficiently genotyping tens to hundreds of SNPs are still crucial for many aspects of this work, including replication of associations.

Determinants of Neonatal Vitamin D Levels as Measured on Neonatal Dried Blood Spot Samples.

Background: Vitamin D deficiency is linked to adverse childhood health outcomes, yet data on the distribution and quantifiable determinants of neonatal 25-hydroxyvitamin D3 (25OHD) concentration, a vitamin D biomarker, are limited.

Objective: Our aim was to identify determinants of neonatal 25OHD concentration, measured using neonatal dried blood spots (DBS).

Methods: A total of 259 ethnically diverse children aged 0-16 years born in Victoria, Australia, were recruited.

Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility.

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.

Methods: We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry.

Sex bias in paediatric autoimmune disease - Not just about sex hormones?

Autoimmune diseases affect up to 10% of the world's population, and approximately 80% of those affected are female. The majority of autoimmune diseases occur more commonly in females, although some are more frequent in males, while others show no bias by sex. The mechanisms leading to sex biased disease prevalence are not well understood.

MicroRNAs in CD4(+) T cell subsets are markers of disease risk and T cell dysfunction in individuals at risk for type 1 diabetes.

MicroRNAs (miRNAs) regulate T cell development and function and the disruption of miRNAs in natural regulatory CD4(+) FOXP3(+) T cells (nTreg) leads to autoimmune disease in mice. To investigate miRNA expression in relation to autoimmune disease risk in humans we sequenced them in purified CD4(+) T cell subsets from individuals at high risk of type 1 diabetes (pre-T1D), as well as other healthy individuals. Differences in miRNA expression patterns were observed between specific T cell subsets and, within subsets, between pre-T1D and healthy individuals.

Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis.

Objective: To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found.

Methods: Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry.