Rheumatic heart disease (RHD) after group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human GAS proteins triggers proinflammatory cardiac valve-reactive T cells. Genome-wide genetic analysis was undertaken 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single-nucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing imputation used to fine-map the leukocyte antigen (HLA)...

A body mass index (BMI) >22kg/m2 is a risk factor for type 2 diabetes (T2D) in Aboriginal Australians. To identify loci associated with BMI and T2D we undertook genome-wide association study using 1,075,436 quality-controlled single nucleotide polymorphisms (SNPs) genotyped (Illumina 2.5M Duo Beadchip) 402 individuals extended pedigrees from Western Australian community. Imputation the thousand genomes (1000G) reference panel analysis to 6,724,284 post quality-control autosomal SNPs. No...

Upon invasion of host cells, the ubiquitous pathogen Toxoplasma gondii manipulates several processes, including re-organization organelles, to create a replicative niche. Host mitochondrial association T. parasitophorous vacuoles is rapid and has roles in modulating immune responses. Here gene expression profiling infected cells reveals enrichment genes involved oxidative phosphorylation (OXPHOS) dysfunction 6 h post-infection. We identified 11 hub (HIF-1α, CASP8, FN1, POU5F1, CD44, ISG15,...

Abstract Background Over 400 million people worldwide are living with a rare disease. Next Generation Sequencing (NGS) identifies potential disease causative genetic variants. However, many identified as variants of uncertain significance (VUS) and require functional laboratory validation to determine pathogenicity, this creates major diagnostic delays . Methods In study we test rapid variant assessment pipeline using CRISPR homology directed repair introduce single nucleotide into inducible...

Genetic analyses, including genome-wide association studies and whole exome sequencing (WES), provide powerful tools for the analysis of complex rare genetic diseases. To date there are no reference data Aboriginal Australians to underpin translation health-based genomic research. Here we a catalogue variants called after exomes 72 individuals depth 20X coverage in ∼80% sequenced nucleotides. We determined 320,976 single nucleotide (SNVs) 47,313 insertions/deletions using Genome Analysis...

Amphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani, with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce incidence rate in Indian subcontinent <1/10,000 population/year. Ability predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress clinical would help monitoring disease outbreaks. Here we...

There are an estimated > 400 million people living with a rare disease globally, genetic variants the cause of approximately 80% cases. Next Generation Sequencing (NGS) rapidly identifies however they often unknown significance. Low throughput functional validation in specialist laboratories is current ad hoc approach for variants, which creating major bottlenecks patient diagnosis. This study investigates application CRISPR gene editing followed by genome wide transcriptomic profiling to...

Visceral leishmaniasis (VL) in Sudan caused by Leishmania donovani is fatal susceptible individuals if untreated. Treatment with sodium stibogluconate (SSG) leads to post-kala-azar dermal (PKDL) 58% of patients. Here, Affymetrix microarrays were used identify genes differentially expressed lymph nodes (N=9 paired samples) pre- and post-treatment SSG. Using the Bioconductor package limma, 438 from 28 869 post-quality-control probe sets (Pnominal ≤.02) post- vs pretreatment. Canonical pathway...

Abstract Background Genomic sequencing in congenital heart disease (CHD) patients often discovers novel genetic variants, which are classified as variants of uncertain significance (VUS). Functional analysis each VUS is required specialised laboratories, to determine whether the causative or not, leading lengthy diagnostic delays. We investigated stem cell cardiac modelling and transcriptomics for purpose variant classification using a GATA4 (p.Arg283Cys) patient with CHD. Methods performed...

Conventional dendritic cells (cDC) resident in the lymphoid organs of mice have been classically divided into CD8+ and CD8neg subsets. It is well established that (DCs) their migratory counterparts periphery comprise cross-presenting cDC1 subset. In contrast, DCs are grouped together heterogeneous cDC2 relatively poor cross-presenters drive more prominent CD4+ T cell responses against exogenous antigens. The discovery X-C motif chemokine receptor 1 (XCR1) as a specific marker DCs, has led to...

Abstract Chronic renal disease (CRD) associated with cardiovascular (CVD) and/or type 2 diabetes (T2D) is a significant problem in Aboriginal Australians. Whole exome sequencing data (N = 72) showed enrichment for ClinVar pathogenic variants gene sets/pathways linking lipoprotein, lipid and glucose metabolism. The top Ingenuity Pathway Analysis canonical pathways were Farsenoid X Receptor Retinoid (FXR/RXR; (P 1.86 × 10 −7 ), Liver (LXR/RXR; P 2.88 −6 atherosclerosis signalling 3.80 ). Top...

Our goal was to identify genetic risk factors for severe otitis media (OM) in Aboriginal Australians.Illumina ® Omni2.5 BeadChip and imputed data were compared between 21 children with OM (multiple episodes chronic suppurative and/or perforations or tympanic sclerosis) 370 individuals without this phenotype, followed by FUnctional Mapping Annotation (FUMA). Exome filtered common (EXaC_all≥0.1) putative deleterious variants influencing protein coding (CADD-scaled scores ≥ 15) used compare 15...

Abstract Visceral leishmaniasis (VL; Leishmania donovani) cases produce interferon-γ and tumor necrosis factor in response to soluble leishmanial antigen (SLA) whole-blood assays. Using transcriptional profiling, we demonstrate the impact of interleukin-10 (IL-10), a cytokine implicated VL, on this response. SLA stimulation identified 28 differentially expressed genes (DEGs), 17/28 single network with TNF as hub. plus anti–IL-10 produced 454 DEGs, 292 TNF, IFNG, NFKBIA, IL6, IL1B hubs...

Toxoplasma gondii uses epigenetic mechanisms to regulate both endogenous and host cell gene expression. To identify genes with putative functions, we developed an in silico pipeline interrogate the T. proteome of 8313 proteins. Step 1 employs PredictNLS NucPred predicted target eukaryotic nuclei. 2 GOLink proteins function based on Gene Ontology terms. This resulted 611 nuclear localised functions. 3 filtered for secretory using SignalP, SecretomeP, experimental data. identified 57 as likely...

Abstract Amphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani , with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce incidence rate in Indian subcontinent &lt;1/10,000 population/year. Ability predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress clinical would help monitoring disease...

Abstract Background Rheumatic heart disease (RHD) following Group A Streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human GAS proteins triggers pro-inflammatory cardiac valve-reactive T-cells. Methods Genome-wide genetic analysis was undertaken 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single nucleotide polymorphisms (SNPs) were genotyped using Illumina HumanCoreExome BeadChips. Direct typing imputation used to...

Whole exome sequencing (WES) is a popular and successful technology which widely used in both research clinical settings. However, there paucity of reference data for Aboriginal Australians to underpin the translation health-based genomic research. Here we provide catalogue variants called after exomes 50 individuals from Northern Territory (NT) Australia compare these 72 previously published Western Australian (WA) population Martu origin. Sequence NT WA samples were processed using an...