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1.
Arthritis Rheumatol ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33452867

RESUMO

BACKGROUND: This study evaluated the activation and functional relevance of inflammasome pathways in AS patients and rodent models and their relationship to dysbiosis. METHODS: Inflammasome pathway was evaluated in the gut and peripheral blood of 40 AS patients by RT-qPCR, IHC, flow cytometry and confocal microscopy and compared to 20 healthy controls (20) and 10 Crohn's disease patients. Silver stain visualized bacteria in human samples and antibiotics were administered to HLA-B27 transgenic rats. The NLRP3 inhibitor MCC950 was administered to SKG mice and ileal and joint tissues assessed by IHC and qRT-PCR. The role of inflammasome in modulating IL-23/IL-17 axis was studied ex-vivo. RESULTS: NLRP3, NLRC4 and AIM2 expression were increased in the gut of HLA-B27 TG rats and reduced by antibiotics (p<0.05). In curdlan-treated SKG mice, NLRP3 blockade prevented ileitis and delayed arthritis onset (p<0.05). Compared to HC,in the ileum of AS patients, NLRP3 (2.33 vs 22.2, p<0.001), NLRC4 (1.90 vs 6.47, p<0.001), AIM2 (2.40 vs 20.8, p<0.001), Caspase-1 (2.53 vs 24.8, p<0.001), IL-1ß (1.07 vs 10.93, p<0.001) and IL-18 (2.56 vs 15.67, p<0.001) were over-expressed and Caspase-1 activity was increased (p<0.01). The score of adherent and invasive mucosa-associated bacteria was higher in AS (p<0.01) and correlated with the expression of inflammasome components in PBMC (p<0.001). NLRP3 expression associated with disease activity (ASDAS-CRP) (r2 =0.28, p<0.01) and IL23A (r2 =0.34, p<0.001). In vitro, inflammasome activation in AS monocytes was paralleled by increased serum levels of IL-1ß and IL18. The induction of IL-23p19, IL-17A, and IL-22 was IL-1ß-dependent. CONCLUSIONS: Inflammasome activation occurs in rodent models and AS patients, is associated with dysbiosis, and is involved in triggering ileitis in SKG mice. Inflammasome drives type 3 cytokine production with an IL-1ß-dependent mechanism in AS patients.

2.
Exp Physiol ; 2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33486778

RESUMO

NEW FINDINGS: What is the central question of this study? The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload? What is the main finding and its importance? Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus. ABSTRACT: Divergent skeletal muscle phenotypes result from chronic resistance-type versus endurance-type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non-overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. -6 ± 18%, mean ± SD, P < 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between-group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload. In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.

3.
Arthritis Rheumatol ; 2020 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-33369221

RESUMO

OBJECTIVES: To investigate the functional consequences of the single nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter associated with ankylosing spondylitis (AS). METHODS: The effects of rs4648889 on allele-specific transcription factor (TF) binding were investigated by DNA pull-down and quantitative mass spectrometry (qMS) with validation by electrophoretic mobility gel shift assays (EMSA), Western blot (WB) analysis of the pulled-down eluates, and chromatin immuno-precipitation (ChIP)-qPCR. Further functional effects were tested by siRNA knockdown of IRF5 followed by qRT-PCR and ELISA to measure mRNA and protein levels of IFNγ. RESULTS: Using nuclear extracts from primary human CD8+ T-cells assessed by qMS, relative TF binding to the AS-risk "A" allele of rs4648889 was increased (3.7-fold, p<0.03) for IKZF3 (aiolos) and components of the NUcleosome Remodeling Deacetylase (NuRD) complex, including Chromodomain-Helicase-DNA-binding protein (CHD) 4 (3.6-fold, p<0.05) and Retinoblastoma-Binding Protein (RBBP) 4 (4.1-fold, p<0.02). In contrast, interferon regulatory factor (IRF) 5 bound significantly less to the A allele (8.2-fold, p=0.003). Validation with WB, EMSA and ChIP-qPCR confirm differential allelic binding for IKZF3, CHD4, RBBP4 and IRF5. Silencing of IRF5 in CD8+ T-cells increased IFNγ mRNA (measured by RT-qPCR (p=0.03) and protein by (ELISA p=0.02). CONCLUSIONS: The findings suggest that the association of rs4648889 with AS reflects allele-specific binding of this enhancer-like region to certain TFs, including IRF5, IKZF3 and members of the NuRD complex. IRF5 may have crucial influences on CD8+ lymphocyte function that could reveal new therapeutic targets in AS.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33367756

RESUMO

CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and non-endocrine tumors. OBJECTIVE: To report two families with germline MAX variants, pheochromocytomas (PC) and multiple other tumors. DESIGN: Clinical, genetic, immunohistochemical, and functional studies. SETTING: University Hospitals in Australia. PARTICIPANTS: Two families with germline MAX variants. INTERVENTIONS: Usual clinical care. MAIN OUTCOME MEASURES: Phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants. RESULTS: Family A has multiple individuals with PC (including bilateral and metastatic disease) and two children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive GHRH staining. Another individual with previously resected PCs has pituitary enlargement and elevated IGF-1. A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss-of-heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss-of-function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multi-gland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. CONCLUSIONS: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as non-endocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.

5.
J Transl Med ; 18(1): 431, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33183308

RESUMO

BACKGROUND: Clinical whole exome sequencing was introduced in an Australian centre in 2017, as an alternative to Sanger sequencing. We aimed to identify predictors of cancer physicians' somatic mutation test ordering behaviour. METHODS: A validated instrument assessed somatic mutation test ordering, genomic confidence, perceived utility of tumour molecular profiling, and percent of patients eligible for targeted therapy. A cash incentive was included in 189/244 questionnaires which were mailed to all Queensland cancer specialists in November 2018. RESULTS: 110 participated (response rate 45%); 54.7% oncologists, and the remainder were surgeons, haematologists and pulmonologists. Oncologists were more likely to respond (p = 0.008), and cash incentive improved the response rate (p < 0.001). 67/102 (65.7%) of physicians ordered ≥ 5 somatic mutation tests annually. Oncologists saw 86.75 unique patients monthly and ordered 2.33 somatic mutation tests (2.2%). An average of 51/110 (46.1%) reported having little/no genomic confidence. Logistic regression identified two significant predictors of somatic mutation test ordering: being an oncologist (OR 3.557, CI 1.338-9.456; p = 0.011) and having greater confidence in interpreting somatic results (OR 5.926, CI 2.230-15.74; p < 0.0001). CONCLUSIONS: Consistent with previous studies, the majority of cancer physicians ordered somatic mutation tests. However, the percentage of patients on whom tests were ordered was low. Almost half respondents reported low genomic confidence. Somatic mutation test ordering was higher amongst oncologists and those with increased confidence in interpreting somatic variants. It is unclear whether genomically confident individuals ordered more tests or whether ordering more tests increased genomic confidence. Educational interventions could improve confidence and enhance test ordering behaviour.

6.
Rheumatology (Oxford) ; 59(Supplement_4): iv58-iv66, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33053195

RESUMO

The axial SpAs (axSpAs) are clearly clinically a heterogeneous set of diseases with markedly varying extra-articular features. These diseases are all highly heritable and have overlapping but differing genetic origins. Shared features include association with HLA class I alleles and genes of the IL-23 pathway, among other things. Significant differences do exist however, both in the genetic loci involved and at specific loci in the individual genetic variants associated with each disease. These similarities and differences are of great interest in regards to disease pathogenesis and treatment development, although individually they are too small in effect to be of prognostic or diagnostic value. Polygenic risk scores, which capture a high proportion of the genetic variation between disorders, have been shown to have clinically useful discriminatory capacity in axSpA. This suggests they have the potential to enable improved disease classification, incorporating basic pathogenic features such as genomics, and ultimately benefitting clinical care. The aim of this article is to review the genetic characteristics of the spectrum of axSpAs and to discuss how this influences our understanding of the disease pathogenesis and the clinical implications of this understanding.

8.
J Infect ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33068628

RESUMO

BACKGROUND: Understanding of the true asymptomatic rate of infection of SARS-CoV-2 is currently limited, as is understanding of the population-based seroprevalence after the first wave of COVID-19 within the UK. The majority of data thus far come from hospitalised patients, with little focus on general population cases, or their symptoms. METHODS: We undertook enzyme linked immunosorbent assay characterisation of IgM and IgG responses against SARS-CoV-2 spike glycoprotein and nucleocapsid protein of 431 unselected general-population participants of the TwinsUK cohort from South-East England, aged 19-86 (median age 48; 85% female). 382 participants completed prospective logging of 14 COVID-19 related symptoms via the COVID Symptom Study App, allowing consideration of serology alongside individual symptoms, and a predictive algorithm for estimated COVID-19 previously modelled on PCR positive individuals from a dataset of over 2 million. FINDINGS: We demonstrated a seroprevalence of 12% (51 participants of 431). Of 48 seropositive individuals with full symptom data, nine (19%) were fully asymptomatic, and 16 (27%) were asymptomatic for core COVID-19 symptoms: fever, cough or anosmia. Specificity of anosmia for seropositivity was 95%, compared to 88% for fever cough and anosmia combined. 34 individuals in the cohort were predicted to be Covid-19 positive using the App algorithm, and of those, 18 (52%) were seropositive. INTERPRETATION: Seroprevalence amongst adults from London and South-East England was 12%, and 19% of seropositive individuals with prospective symptom logging were fully asymptomatic throughout the study. Anosmia demonstrated the highest symptom specificity for SARS-CoV-2 antibody response. FUNDING: NIHR BRC, CDRF, ZOE global LTD, RST-UKRI/MRC.

9.
Sci Rep ; 10(1): 17636, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077849

RESUMO

Birdshot retinochoroidopathy occurs exclusively in individuals who are HLA-A29 positive. The mechanism to account for this association is unknown. The gut microbiome has been causally implicated in many immune-mediated diseases. We hypothesized that HLA-A29 would affect the composition of the gut microbiome, leading to a dysbiosis and immune-mediated eye disease. Fecal and intestinal biopsy samples were obtained from 107 healthy individuals from Portland, Oregon environs, 10 of whom were HLA-A29 positive, undergoing routine colonoscopy. Bacterial profiling was achieved via 16S rRNA metabarcoding. Publicly available whole meta-genome sequencing data from the Human Microbiome Project (HMP), consisting of 298 healthy controls mostly of US origin, were also interrogated. PERMANOVA and sparse partial least squares discriminant analysis (sPLSDA) demonstrated that subjects who were HLA-A29 positive differed in bacterial species composition (beta diversity) compared to HLA-A29 negative subjects in both the Portland (p = 0.019) and HMP cohorts (p = 0.0002). The Portland and HMP cohorts evidenced different subsets of bacterial species associated with HLA-A29 status, likely due to differences in the metagenomic techniques employed. The functional composition of the HMP cohort did not differ overall (p = 0.14) between HLA-A29 positive and negative subjects, although some distinct pathways such as heparan sulfate biosynthesis showed differences. As we and others have shown for various HLA alleles, the HLA allotype impacts the composition of the microbiome. We hypothesize that HLA-A29 may predispose chorioretinitis via an altered gut microbiome.

10.
Radiology ; 297(2): 474-481, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32897162

RESUMO

Background Dialysis maintenance interventions account for billions of dollars in U.S. Medicare spending and are performed by multiple medical specialties. Whether Medicare costs differ by physician specialty is, to the knowledge of the authors, not known. Purpose To assess patency-adjusted costs of endovascular dialysis access maintenance by physician specialty. Materials and Methods In this retrospective longitudinal cohort study, patients who were beneficiaries of Medicare undergoing their first arteriovenous access placement in 2009 were identified by using billing codes in the 5% Limited Data Set. By tracking their utilization data through 2014, postintervention primary patency and aggregate payments associated with maintenance interventions were calculated. Unadjusted payments per year of access patency gain were compared across physician specialty. A general linear mixed-effects model adjusted for covariates was used, as follows: patient characteristics, access type (fistula vs graft), clinical severity, type of intervention (angioplasty, stent, thrombolysis), clinical location (hospital outpatient vs office-based laboratory), and resource utilization (operating room use, anesthesia use). Results First arteriovenous access was performed in 1479 beneficiaries (mean age, 63 years ± 15 [standard deviation]; 820 men) in 2009. Through 2014, 8166 maintenance interventions were performed in this cohort. Unadjusted mean Medicare payments for each incremental year of patency were as follows: $71 000 for radiologists, $89 000 for nephrologists, and $174 000 for surgeons. Billing for operating room (41.8% [792 of 1895], surgery; 10.2% [277 of 2709], nephrology; and 31.1% [1108 of 3562], radiology) and anesthesia (19.9% [377 of 1895], surgery; 2.6% [70 of 2709], nephrology; 4.7% [170 of 3562], radiology) varied by specialty and accounted for 407% and 132% higher payments, respectively. After adjusting for clinical severity and location, type of intervention, and resource utilization, nephrologists and surgeons had 59% (95% confidence interval: 44%, 73%; P < .001) and 57% (95% confidence interval: 43%, 72%; P < .001) higher payments, respectively, for the same patency gain compared with radiologists. Operating room use and anesthesia services were major drivers of higher cost, with 407% (95% confidence interval: 374%, 443%; P < .001) and 132% (95% confidence interval: 116%, 150%; P < .001) higher costs, respectively. Conclusion Patency-adjusted payments for hemodialysis access maintenance differed by physician specialty, driven partly by discrepant rates of billing for operating room and anesthesia use. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by White in this issue.

11.
Twin Res Hum Genet ; 23(4): 204-213, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32755526

RESUMO

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10-10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10-6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10-3; p = 2.29 × 10-3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10-3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

12.
PLoS Genet ; 16(8): e1008906, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804949

RESUMO

The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.


Assuntos
Epistasia Genética , Antígenos HLA/genética , Receptores KIR/genética , Espondilite Anquilosante/genética , Alelos , Aminopeptidases/genética , Humanos , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo de Nucleotídeo Único
13.
Orphanet J Rare Dis ; 15(1): 193, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727600

RESUMO

BACKGROUND: Genetic contributors to cardiac arrhythmias are often found in cardiovascular conduction pathways and ion channel proteins. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disease of massive heterotopic ossification caused by a highly recurrent R206H mutation in ACVR1/ALK2. This mutation causes abnormal activation of the bone morphogenetic protein (BMP) pathway in response to Activin A. Prior studies suggested increased risks of cardiopulmonary complications in FOP. We examined participants in a Natural History Study (NHS) of FOP (ClinicalTrials.gov #NCT02322255) to better understand their cardiovascular status. METHODS: The NHS is an ongoing 3 year international multi-center longitudinal study of 114 patients (ages 4-56 years) with genetically confirmed ACVR1/ALK2R206H FOP. Patients were clinically assessed at baseline and 12 months. Electrocardiograms (ECGs) were reviewed in a central ECG laboratory. Conduction abnormalities were compared against clinical data collected in the NHS, and echocardiograms collected from NHS and non-NHS patients. RESULTS: Conduction abnormalities were present in 45.3% of baseline ECGs, with the majority of abnormalities classified as nonspecific intraventricular conduction delay (37.7%). More specifically, 22.2% of patients > 18 years old had conduction abnormalities, which was significantly higher than a prior published study of a healthy population (5.9%; n = 3978) (p < 0.00001). Patients with FOP < 18 years old also had a high prevalence of conduction abnormalities (62.3%). The 12-month follow up data was similar to baseline results. Conduction abnormalities did not correlate with chest wall deformities, scoliosis, pulmonary function test results, or increased Cumulative Analog Joint Involvement Scale scores. Echocardiograms from 22 patients with FOP revealed 8 with structural cardiac abnormalities, only 1 of which correlated with a conduction abnormality. CONCLUSIONS: We found that patients with FOP may have subclinical conduction abnormalities manifesting on ECG, independent of heterotopic ossification. Although clinically significant heart disease is not typically associated with FOP, and the clinical implications for cardiovascular risk remain unclear, knowledge about ECG and echocardiogram changes is important for clinical care and research trials in patients with FOP. Further studies on how ACVR1/ALK2R206H affects cardiac health will help elucidate the underlying mechanism.

14.
Nat Rev Rheumatol ; 16(8): 448-463, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32606474

RESUMO

The term axial spondyloarthritis (axSpA) encompasses a heterogeneous group of diseases that have variable presentations, extra-articular manifestations and clinical outcomes, and that will respond differently to treatments. The prototypical type of axSpA, ankylosing spondylitis, is thought to be caused by interaction between the genetically primed host immune system and gut microbiota. Currently used biomarkers such as HLA-B27 status, C-reactive protein and erythrocyte sedimentation rate have, at best, moderate diagnostic and predictive value. Improved biomarkers are needed for axSpA to assist with early diagnosis and to better predict treatment responses and long-term outcomes. Advances in a range of 'omics' technologies and statistical approaches, including genomics approaches (such as polygenic risk scores), microbiome profiling and, potentially, transcriptomic, proteomic and metabolomic profiling, are making it possible for more informative biomarker sets to be developed for use in such clinical applications. Future developments in this field will probably involve combinations of biomarkers that require novel statistical approaches to analyse and to produce easy to interpret metrics for clinical application. Large publicly available datasets from well-characterized case-cohort studies that use extensive biological sampling, particularly focusing on early disease and responses to medications, are required to establish successful biomarker discovery and validation programmes.


Assuntos
Biomarcadores/sangue , Espondilartrite/sangue , Humanos
15.
Nat Rev Rheumatol ; 16(10): 545-546, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32690928
16.
Life Sci Alliance ; 3(7)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32518073

RESUMO

At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.

17.
Invest Ophthalmol Vis Sci ; 61(6): 3, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32492107

RESUMO

Purpose: Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. Methods: We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering. Results: We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10-8, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10-7, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10-7, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10-6, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10-7, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10-6, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10-7, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. Conclusions: We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.

18.
EBioMedicine ; 57: 102840, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32580138

RESUMO

BACKGROUND: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease. METHODS: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS. FINDINGS: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 × 10-8

19.
Ann Rheum Dis ; 79(8): 1044-1054, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404344

RESUMO

BACKGROUND: The human enthesis conventional T cells are poorly characterised. OBJECTIVES: To study the biology of the conventional T cells in human enthesis. METHODS: CD4+ and CD8+ T cells were investigated in 25 enthesis samples using immunofluorescence, cytometrically, bulk RNAseq and quantitative real-time PCR following anti-CD3/CD28 bead stimulation to determine interleukin (IL)-17A and tumour necrosis factor (TNF) levels. T-cell receptor (TCR) repertoires were characterised and a search for putative T-cell reactivity was carried out using TCR3 database. The impact of pharmacological antagonism with retinoic acid receptor-related orphan nuclear receptor gamma t inhibitor (RORγti), methotrexate and phosphodiesterase type 4 inhibitor (PDE4i) was investigated. RESULTS: Immunofluorescence and cytometry suggested entheseal resident CD4+ and CD8+ T cells with a resident memory phenotype (CD69+/CD45RA-) and tissue residency gene transcripts (higher NR4A1/AhR and lower KLF2/T-bet transcripts). Both CD4+ and CD8+ T cells showed increased expression of immunomodulatory genes including IL-10 and TGF-ß compared with peripheral blood T cells with entheseal CD8+ T cells having higher CD103, CD49a and lower SIPR1 transcript that matched CD4+ T cells. Following stimulation, CD4+ T cells produced more TNF than CD8+ T cells and IL-17A was produced exclusively by CD4+ T cells. RNAseq suggested both Cytomegalovirus and influenza A virus entheseal resident T-cell clonotype reactivity. TNF and IL-17A production from CD4+ T cells was effectively inhibited by PDE4i, while RORγti only reduced IL-17A secretion. CONCLUSIONS: Healthy human entheseal CD4+ and CD8+ T cells exhibit regulatory characteristics and are predicted to exhibit antiviral reactivity with CD8+ T cells expressing higher levels of transcripts suggestive of tissue residency. Inducible IL-17A and TNF production can be robustly inhibited in vitro.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ligamentos Articulares/imunologia , Linfócitos T Reguladores/imunologia , Tendões/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Feminino , Humanos , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/imunologia
20.
Front Genet ; 11: 461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32457804

RESUMO

Causal attributions are important determinants of how health threats are processed and affect health-related behaviors. To date, there has been no research on causal attributions in genetic conditions in Aboriginal Australians. Forty members of a large Aboriginal Australian family with Marfan syndrome (MFS) were invited to participate in an ethically approved study exploring causal attributions, including perceived causes of phenotypic variability within the family. Eighteen individuals consented to conduct semi-structured qualitative interviews, which were recorded, transcribed verbatim and analyzed thematically. Most participants knew that MFS was genetic, but there were diverse theories about inheritance, including beliefs that it skipped generations, was affected by birth order and/or gender, and that it co-occurred with inheritance of blue eyes within this family. The mutation was thought to have been inherited from British settlers and initially triggered by disease or diet. Factors believed to modify disease severity included other genes and lifestyle factors, particularly alcohol and substance abuse and stress. Generally, this family did not endorse "blaming" chance or a higher power for phenotypic variability, though some felt that the spirits or a deity may have played a role. In conclusion, although participants knew MFS was a genetic condition, many speculated about the role of non-genetic causes in initiating the original mutation; and the gene-environment interaction was thought to affect severity. This study demonstrates a successful approach for exploring causal attributions in other genetic conditions in First Australians.

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