Publications by authors named "Matthew A Brown"

343 Publications

Reply to Niv Ben-Shabat: Mortality in AS according to treatment.

Arthritis Care Res (Hoboken) 2021 Aug 26. Epub 2021 Aug 26.

Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.

We read with great interest the article by Niv Ben-Shabat et al. in Arthritis Care and Research titled "Mortality in ankylosing spondylitis according to treatment: a nationwide retrospective cohort study of 5900 patients from Israel" (1). The study concludes that ankylosing spondylitis (AS) is associated with reduced life expectancy, but not amongst the small subgroup of AS patients treated with TNF-inhibitors. We have concerns regarding the study design and analyses that underpin these findings.
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http://dx.doi.org/10.1002/acr.24773DOI Listing
August 2021

Identifying Trajectories of Radiographic Spinal Disease in Ankylosing Spondylitis: A 15-year follow up study of the PSOAS Cohort.

Rheumatology (Oxford) 2021 Aug 24. Epub 2021 Aug 24.

Department of Medicine-Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, CA, USA.

Objectives: Little is known with certainty about the natural history of spinal disease progression in Ankylosing Spondylitis (AS). Our objective was to discover if there were distinct patterns of change in vertebral involvement over time and to study associated clinical factors.

Methods: Data were analyzed from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) observational cohort. All patients met modified New York Criteria for AS and had ≥2 sets of radiographs scored by modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) by two independent readers between 2002-2017. Group-based trajectory modeling (GBTM) was used to classify patients into distinct groups of longitudinal mSASSS considering sociodemographic and clinical covariables. The optimal trajectory model and number of trajectories was selected using Nagin's Bayesian information criterion (BIC).

Results: A total of 561 patients with 1618 radiographs was analyzed. The optimum number of trajectory groups identified was four (BIC -4062). These groups were subsequently categorized as: non-progressors (204 patients), late-progressors (147 patients), early-progressors (107 patients) and rapid-progressors (103 patients). Baseline predictors associated with higher spinal disease burden groups included: baseline mSASSS, male gender, longer disease duration, elevated C-reactive protein and smoking history. In addition, time-varying anti-TNF use per year was associated with decreased mSASSS progression only in the rapid-progressor group.

Conclusions: GBTM identified 4 distinct patterns of spinal disease progression in the PSOAS cohort. Male gender, longer disease duration, elevated C-reactive protein and smoking were associated with higher spinal disease groups. Independent confirmation in other AS cohorts is needed to confirm these radiographic patterns.
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http://dx.doi.org/10.1093/rheumatology/keab661DOI Listing
August 2021

Intra-Aortic Balloon Pump as a Bridge to Durable Left Ventricular Assist Device.

J Am Heart Assoc 2021 Aug 26;10(15):e019376. Epub 2021 Jul 26.

Georgetown University School of Medicine Washington DC.

Left ventricular assist devices (LVAD) are increasingly being used as destination therapy in patients with Stage D heart failure. It has been reported that a majority of patients who receive a durable LVAD (dLVAD) present in cardiogenic shock due to decompensated heart failure (ADHF-CS). As it stands, there is no consensus on the optimal management strategy for patients presenting with ADHF. Bridging with intra-aortic balloon pumps (IABPs) continues to be a therapeutic option in patients with hemodynamic instability due to cardiogenic shock. The majority of data regarding the use of IABP in cardiogenic shock come from studies in patients presenting with acute myocardial infarction with cardiogenic shock and demonstrates that there is no benefit of routine IABP use in this patient population. However, the role of IABPs as a bridge to dLVAD in ADHF-CS has yet to be determined. The hemodynamic changes seen in acute myocardial infarction with cardiogenic shock are known to be different and more acutely impaired than those presenting with ADHF-CS as evidenced by differences in pressure/volume loops. Thus, data should not be extrapolated across these 2 very different disease processes. The aim of this review is to describe results from contemporary studies examining the use of IABPs as a bridge to dLVAD in patients with ADHF-CS. Retrospective evidence from large registries suggests that the use of IABP as a bridge to dLVAD is feasible and safe when compared with other platforms of temporary mechanical circulatory support. However, there is currently a paucity of high-quality evidence examining this increasingly important clinical question.
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http://dx.doi.org/10.1161/JAHA.120.019376DOI Listing
August 2021

Germline ERBB3 mutation in familial non-small cell lung carcinoma: Expanding ErbB's role in oncogenesis.

Hum Mol Genet 2021 Jul 19. Epub 2021 Jul 19.

Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102.

Introduction: Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2.

Materials And Methods: Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and sub-cellular localisation were assessed, and cellular proliferation, pAkt/Akt, and pERK levels determined.

Results: A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80kD form (which enhances proliferation) compared to the full-length (180kD) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localisation pre- and post-EGF stimulation; however, EGFR levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared to wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 minutes post-stimulation compared to wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic.

Conclusions: This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.
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http://dx.doi.org/10.1093/hmg/ddab172DOI Listing
July 2021

The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study.

Lancet Rheumatol 2021 Sep 8;3(9):e627-e637. Epub 2021 Jul 8.

St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, King's College London, London, UK.

Background: Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose.

Methods: In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination.

Findings: Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31-52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67-87] of 77) than in controls (17 [100%; 80-100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21-73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40-236]) than in controls (317 [213-487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141-418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls.

Interpretation: Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness.

Funding: UK National Institute for Health Research.
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http://dx.doi.org/10.1016/S2665-9913(21)00212-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266273PMC
September 2021

Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.

Ann Rheum Dis 2021 09 20;80(9):1168-1174. Epub 2021 Apr 20.

Rheumatology Department, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Objective: We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain.

Methods: PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), and sacroiliac MRI.

Results: In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for these values were 51.9% and 97.9%, respectively.

Conclusions: PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.
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http://dx.doi.org/10.1136/annrheumdis-2020-219446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364478PMC
September 2021

Ankylosing spondylitis: an autoimmune or autoinflammatory disease?

Nat Rev Rheumatol 2021 07 10;17(7):387-404. Epub 2021 Jun 10.

Dipartimento di Medicina di Precisione, Università della Campania L. Vanvitelli, Naples, Italy.

Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.
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http://dx.doi.org/10.1038/s41584-021-00625-yDOI Listing
July 2021

Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes.

Ann Rheum Dis 2021 Apr 1. Epub 2021 Apr 1.

Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Andalucía, Spain.

Objective: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes.

Methods: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA).

Results: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with and , and revealed a novel association of . Stratified analyses showed specific associations of with lcSSc, and an exclusive association of with dcSSc. Similarly, private associations were detected in and confirmed the previously reported association of with ACA-positive patients, as opposed to the and alleles associated with ATA presentation.

Conclusions: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.
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http://dx.doi.org/10.1136/annrheumdis-2021-219884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292594PMC
April 2021

Repeated Spinal Mobility Measures and Their Association With Radiographic Damage in Ankylosing Spondylitis.

ACR Open Rheumatol 2021 Jun 27;3(6):413-421. Epub 2021 May 27.

John P. and Katherine G. McGovern Medical School, The University of Texas Health Science Center, Houston.

Objective: We sought to explore the relationship between changes in repeated mobility measures and spinal structural progression in patients with ankylosing spondylitis (AS) over time.

Methods: We studied patients with AS from the PSOAS (Prospective Study of Outcomes in AS) cohort and performed longitudinal multivariable regression modeling to assess the relationship of structural damage measured by their regional (cervical or lumbar) modified Stoke AS Spinal Score(mSASSS) and selected cervical (eg, cervical rotation, lateral bending, and occiput-to-wall distance) and lumbar spinal mobility measures (eg, Schöber's test and lumbar lateral bending) that were collected at least every 2 years from 2003 to 2019.

Results: The median length of follow-up for our 518 patients with cervical mSASSS measurements and 573 with lumbar mSASSS measurements was 4.08 (interquartile range [IQR] 2.25-6.67) and 4.17 (IQR 2.25-6.67) years, respectively. Among the mobility measures, based on multivariable regression models adjusting for clinical/demographic variables and C-reactive protein, we did not observe meaningful associations between changes in spinal mobility with their respective regional mSASSS. Baseline mSASSS, male sex, increased C-reactive protein (CRP), and longer disease duration were associated with increased longitudinal mSASSS in all analyses.

Conclusion: Our study shows that 2-year changes in individual spinal mobility measures are not reliably associated with increased, longitudinal, AS-related spinal structural progression. We also confirmed the relationship of baseline mSASSS, sex, CRP, and disease duration with AS-related structural spinal progression over time.
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http://dx.doi.org/10.1002/acr2.11261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207687PMC
June 2021

A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young.

JCI Insight 2021 Jul 8;6(13). Epub 2021 Jul 8.

Faculty of Medicine, University of Queensland, Herston, Queensland, Australia.

Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β cell function. The mechanisms underlying MODY include β cell KATP channel dysfunction (e.g., KCNJ11 [MODY13] or ABCC8 [MODY12] mutations); however, no other β cell channelopathies have been associated with MODY to date. Here, we have identified a nonsynonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and β cell-restricted K+ channel transcript, encoding the two-pore-domain K+ channel TALK-1. Whole-cell K+ currents demonstrated a large gain of function with TALK-1 Leu114Pro compared with TALK-1 WT, due to greater single-channel activity. Glucose-stimulated membrane potential depolarization and Ca2+ influx were inhibited in mouse islets expressing TALK-1 Leu114Pro with less endoplasmic reticulum Ca2+ storage. TALK-1 Leu114Pro significantly blunted glucose-stimulated insulin secretion compared with TALK-1 WT in mouse and human islets. These data suggest that KCNK16 is a previously unreported gene for MODY.
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http://dx.doi.org/10.1172/jci.insight.138057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410089PMC
July 2021

Comparative efficacy and safety of the Captus device for inferior vena cava filter retrieval.

Clin Imaging 2021 Sep 30;77:202-206. Epub 2021 Apr 30.

Department of Radiology, Division of Interventional Radiology, University of Colorado Anschutz Medical Campus, Mail Stop # L954, 12401 E. 17th Avenue, Aurora, CO 80045, United States of America. Electronic address:

Purpose: Retrievable inferior vena cava filters (IVCF) have been increasingly used for mechanical pulmonary embolism prophylaxis since their development. The Captus Vascular Retrieval System (Avantec Vascular, Sunnyvale, California) is a new device developed for retrieval of IVCF. This study compared the safety and efficacy of the new Captus device against the existing EnSnare Endovascular Snare System (Merit Medical, South Jordan, Utah) for IVCF retrieval.

Methods: Patients undergoing IVCF retrieval at a single institution between July 2015 and July 2020 were retrospectively identified. All adult patients (>18 years) undergoing filter retrieval with either Captus or Ensnare were included. Technical success and complications were compared by device. A complexity score was assigned to each case to adjust for selection bias. Logistic regression was used to model the association between device type and primary technical success.

Results: 99 IVCF retrievals met inclusion criteria, 59 with Captus and 40 with Ensnare. The majority of the cohort consisted of low complexity cases (n = 51, 86% Captus versus n = 31, 78% Ensnare; p = 0.28). Technical success for low and medium complexity retrievals was 88% and 62% with Captus and 96% and 33% with Ensnare. There was no significant association between device type and technical success, adjusting for case complexity (Captus OR 0.55, 95% CI 0.08-2.72, p = 0.49). There were no device-related complications.

Conclusion: No statistically significant difference in device technical success or complications between the Ensnare and Captus devices for uncomplicated IVCF retrieval.

Precis: The Captus Vascular Retrieval System is a new device for IVC filter retrieval which has similar technical success to the existing EnSnare.
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http://dx.doi.org/10.1016/j.clinimag.2021.04.024DOI Listing
September 2021

Genome wide association study of response to interval and continuous exercise training: the Predict-HIIT study.

J Biomed Sci 2021 May 13;28(1):37. Epub 2021 May 13.

Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Kelvin Grove, Brisbane, QLD, Australia.

Background: Low cardiorespiratory fitness (V̇O) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O, there is considerable inter-individual variability in the V̇O response to the same dose of exercise. Understanding how genetic factors contribute to V̇O training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇Opeak response following exercise training.

Methods: Participant change in objectively measured V̇Opeak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10) with the magnitude of V̇Opeak response. Findings were tested in an independent validation study (n = 39) and compared to previous research.

Results: No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇Opeak individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇Opeak response that reached suggestive significance (P < 1 × 10). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10). A PPS created from the 12 lead SNPs was unable to predict V̇Opeak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10) and the validation study (P <  × 10), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent.

Conclusions: Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇Opeak response variance, and whether genomic predictors for V̇Opeak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .
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http://dx.doi.org/10.1186/s12929-021-00733-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117553PMC
May 2021

Ethnoracial Disparity in Hospital Survival following Transjugular Intrahepatic Portosystemic Shunt Creation for Acute Variceal Bleeding in the United States.

J Vasc Interv Radiol 2021 07 24;32(7):941-949.e3. Epub 2021 Apr 24.

Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Radiology, University of Southern California, Los Angeles, California.

Purpose: To investigate the magnitude of racial/ethnic differences in hospital mortality after transjugular intrahepatic portosystemic shunt (TIPS) creation for acute variceal bleeding and whether hospital care processes contribute to them.

Methods: Patients aged ≥18 years undergoing TIPS creation for acute variceal bleeding in the United States (n = 10,331) were identified from 10 years (2007-2016) available in the National Inpatient Sample. Hierarchical logistic regression was used to examine the relationship between patient race and inpatient mortality, controlling for disease severity, treatment utilization, and hospital characteristics.

Results: A total of 6,350 (62%) patients were White, 1,780 (17%) were Hispanic, and 482 (5%) were Black. A greater proportion of Black patients were admitted to urban teaching hospitals (Black, n = 409 (85%); Hispanic, n = 1,310 (74%); and White, n = 4,802 (76%); P < .001) and liver transplant centers (Black, n = 215 (45%); Hispanic, n = 401 (23%); and White, n = 2,267 (36%); P < .001). Being Black was strongly associated with mortality (Black, 32% vs non-Black, 15%; odds ratio, 3.0 [95% confidence interval, 1.6-5.8]; P = .001), as assessed using the risk-adjusted regression model. This racial disparity disappeared in a sensitivity analysis including only patients with a maximum Child-Pugh score of 13 (odds ratio 1.2 [95% confidence interval, 0.4-3.6]; P = .68), performed to compensate for the absence of Model for End-stage Liver Disease scores. Ethnoracial differences in access to teaching hospitals, liver transplant centers, first-line endoscopy, and transfusion did not significantly contribute (P > .05) to risk-adjusted mortality.

Conclusions: Black patients have a 2-fold higher inpatient mortality than non-Black patients following TIPS creation for acute variceal bleeding, possibly related to greater disease severity before the procedure.
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http://dx.doi.org/10.1016/j.jvir.2021.02.027DOI Listing
July 2021

Low responders to endurance training exhibit impaired hypertrophy and divergent biological process responses in rat skeletal muscle.

Exp Physiol 2021 Mar 5;106(3):714-725. Epub 2021 Feb 5.

Faculty of Health Sciences and Medicine, Bond University, Robina, Gold Coast, Queensland, Australia.

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.
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http://dx.doi.org/10.1113/EP089301DOI Listing
March 2021

Inflammasome Activation in Ankylosing Spondylitis Is Associated With Gut Dysbiosis.

Arthritis Rheumatol 2021 07 25;73(7):1189-1199. Epub 2021 May 25.

Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Objective: We undertook this study to evaluate the activation and functional relevance of inflammasome pathways in ankylosing spondylitis (AS) patients and rodent models and their relationship to dysbiosis.

Methods: An inflammasome pathway was evaluated in the gut and peripheral blood from 40 AS patients using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), flow cytometry, and confocal microscopy, and was compared to that of 20 healthy controls and 10 patients with Crohn's disease. Bacteria was visualized using silver stain 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 were assessed by IHC analysis and real-time qRT-PCR. The role of inflammasome in modulating the interleukin-23 (IL-23)/IL-17 axis was studied ex vivo.

Results: Expression levels of Nlrp3, Nlrc4, and Aim2 were increased in the gut of HLA-B27-transgenic rats and reduced by antibiotic treatment (P < 0.05). In curdlan-treated SKG mice, NLRP3 blockade prevented ileitis and delayed arthritis onset (P < 0.05). Compared to healthy controls, AS patients demonstrated overexpression of NLRP3 (fold induction 2.33 versus 22.2; P < 0.001), NLRC4 (fold induction 1.90 versus 6.47; P < 0.001), AIM2 (fold induction 2.40 versus 20.8; P < 0.001), CASP1 (fold induction 2.53 versus 24.8; P < 0.001), IL1B (fold induction 1.07 versus 10.93; P < 0.001), and IL18 (fold induction 2.56 versus 15.67; P < 0.001) in the ileum, 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 peripheral blood mononuclear cells (P < 0.001). NLRP3 expression was associated with disease activity (the Ankylosing Spondylitis Disease Activity Score using the C-reactive protein level) (r = 0.28, P < 0.01) and with IL23A expression (r = 0.34, P < 0.001). In vitro, inflammasome activation in AS monocytes was paralleled by increased serum levels of IL-1β and IL-18. Induction of IL23A, IL17A, and IL22 was IL-1β-dependent.

Conclusion: Inflammasome activation occurs in rodent models of AS and in AS patients, is associated with dysbiosis, and is involved in triggering ileitis in SKG mice. Inflammasomes drive type III cytokine production with an IL-1β-dependent mechanism in AS patients.
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http://dx.doi.org/10.1002/art.41644DOI Listing
July 2021

Functional Genomic Analysis of a RUNX3 Polymorphism Associated With Ankylosing Spondylitis.

Arthritis Rheumatol 2021 06 2;73(6):980-990. Epub 2021 May 2.

NIHR Oxford Musculoskeletal Biomedical Research Unit, Botnar Research Centre, Nuffield Orthopaedic Centre, NIHR Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.

Objective: To investigate the functional consequences of the single-nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter associated with susceptibility to ankylosing spondylitis (AS).

Methods: Using nuclear extracts from Jurkat cells and primary human CD8+ T cells, the effects of rs4648889 on allele-specific transcription factor (TF) binding were investigated by DNA pull-down assay and quantitative mass spectrometry (qMS), with validation by electrophoretic mobility shift assay (EMSA), Western blotting of the pulled-down eluates, and chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction (qPCR) analysis. Further functional effects were tested by small interfering RNA knockdown of the gene for interferon regulatory factor 5 (IRF5), followed by reverse transcription-qPCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) to measure the levels of IFNγ messenger RNA (mRNA) and protein, respectively.

Results: In nuclear extracts from CD8+ T cells, results of qMS showed that relative TF binding to the AS-risk A allele of rs4648889 was increased 3.7-fold (P < 0.03) for Ikaros family zinc-finger protein 3 (IKZF3; Aiolos) and components of the NuRD complex, including chromodomain helicase DNA binding protein 4 (CHD4) (3.6-fold increase; P < 0.05) and retinoblastoma binding protein 4 (RBBP4) (4.1-fold increase; P < 0.03). In contrast, IRF5 bound significantly more to the AS-protective G allele compared to the AS-risk A allele (fold change 8.2; P = 0.003). Validation with Western blotting, EMSA, and ChIP-qPCR confirmed the differential allelic binding of IKZF3, CHD4, RBBP4, and IRF5. Silencing of IRF5 in CD8+ T cells increased the levels of IFNγ mRNA as measured by RT-qPCR (P = 0.03) and IFNγ protein as measured by ELISA (P = 0.02).

Conclusion: These 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 the functions of CD8+ lymphocytes, a finding that could reveal new therapeutic targets for the management of AS.
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http://dx.doi.org/10.1002/art.41628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251554PMC
June 2021

Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

J Clin Endocrinol Metab 2021 03;106(4):1163-1182

Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, Woolloongabba, Australia.

Context: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors.

Objective: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors.

Methods: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were 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 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (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, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified.

Conclusion: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.
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http://dx.doi.org/10.1210/clinem/dgaa957DOI Listing
March 2021

Factors influencing cancer genetic somatic mutation test ordering by cancer physician.

J Transl Med 2020 11 12;18(1):431. Epub 2020 Nov 12.

The Dermatology Research Group, University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102, Australia.

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.
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http://dx.doi.org/10.1186/s12967-020-02610-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663861PMC
November 2020

HLA-A alleles including HLA-A29 affect the composition of the gut microbiome: a potential clue to the pathogenesis of birdshot retinochoroidopathy.

Sci Rep 2020 10 19;10(1):17636. Epub 2020 Oct 19.

Department of Medicine, Oregon Health & Science University, Portland, OR, USA.

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.
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http://dx.doi.org/10.1038/s41598-020-74751-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572371PMC
October 2020

Estimates of the rate of infection and asymptomatic COVID-19 disease in a population sample from SE England.

J Infect 2020 12 15;81(6):931-936. Epub 2020 Oct 15.

Department of Twin Research, King's College London, St Thomas' Hospital, London SE1 7EH, UK.

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.
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http://dx.doi.org/10.1016/j.jinf.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557299PMC
December 2020

Genetics and the axial spondyloarthritis spectrum.

Rheumatology (Oxford) 2020 10;59(Suppl4):iv58-iv66

Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, QLD, Australia.

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.
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http://dx.doi.org/10.1093/rheumatology/keaa464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566537PMC
October 2020

Intracardiac Echocardiography-Guided TIPS: A Primer for New Operators.

Semin Intervent Radiol 2020 Oct 1;37(4):405-413. Epub 2020 Oct 1.

Division of Vascular and Interventional Radiology, University of Colorado School of Medicine, Aurora, Colorado.

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http://dx.doi.org/10.1055/s-0040-1715875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540636PMC
October 2020

Cost Analysis of Dialysis Access Maintenance Interventions across Physician Specialties in U.S. Medicare Beneficiaries.

Radiology 2020 11 8;297(2):474-481. Epub 2020 Sep 8.

From the Department of Radiology, University of Colorado Anschutz Medical Campus, 12401 E 17th Ave, Aurora, CO 80045 (P.S.T., M.A.B., J.P.B., P.J.R., R.K.R.); Department of Biostatistics, University of Colorado School of Public Health, Aurora, Colo (A.M.J., R.C.L.); Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Md (K.H.); and Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Ga (R.L.D.).

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%; < .001) and 57% (95% confidence interval: 43%, 72%; < .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%; < .001) and 132% (95% confidence interval: 116%, 150%; < .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 See also the editorial by White in this issue.
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http://dx.doi.org/10.1148/radiol.2020192403DOI Listing
November 2020

Epistatic interactions between killer immunoglobulin-like receptors and human leukocyte antigen ligands are associated with ankylosing spondylitis.

PLoS Genet 2020 08 17;16(8):e1008906. Epub 2020 Aug 17.

Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

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.
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http://dx.doi.org/10.1371/journal.pgen.1008906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451988PMC
August 2020

Septic Shock: A Genomewide Association Study and Polygenic Risk Score Analysis.

Twin Res Hum Genet 2020 08 5;23(4):204-213. Epub 2020 Aug 5.

The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia.

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.
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http://dx.doi.org/10.1017/thg.2020.60DOI Listing
August 2020

Patients with ACVR1 mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of Fibrodysplasia Ossificans Progressiva.

Orphanet J Rare Dis 2020 07 29;15(1):193. Epub 2020 Jul 29.

Division of Endocrinology and Metabolism, the UCSF Metabolic Bone Clinic, University of California- San Francisco, 513 Parnassus Ave., HSE901G, San Francisco, CA, 94143-0794, USA.

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/ALK2 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/ALK2 affects cardiac health will help elucidate the underlying mechanism.
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http://dx.doi.org/10.1186/s13023-020-01465-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389682PMC
July 2020

Genetic risk scores in inflammatory arthritis: a new era?

Nat Rev Rheumatol 2020 10;16(10):545-546

Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1038/s41584-020-0473-6DOI Listing
October 2020

Biomarker development for axial spondyloarthritis.

Nat Rev Rheumatol 2020 08 30;16(8):448-463. Epub 2020 Jun 30.

Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1038/s41584-020-0450-0DOI Listing
August 2020

Identification of susceptibility variants to benign childhood epilepsy with centro-temporal spikes (BECTS) in Chinese Han population.

EBioMedicine 2020 Jul 21;57:102840. Epub 2020 Jun 21.

Guy's & St Thomas' NHS Foundation Trust and King's College London, NIHR Biomedical Research Centre, London, England United Kingdom. Electronic address:

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
Interpretation: This study shows that BECTS risk is at least partially heritable and due to common genetic variants. Additionally, we demonstrate that BECTS risk is substantially increased by maternal smoking around birth.
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http://dx.doi.org/10.1016/j.ebiom.2020.102840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317238PMC
July 2020

A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.

Nat Commun 2020 06 19;11(1):3150. Epub 2020 Jun 19.

The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.

MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl, that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).
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http://dx.doi.org/10.1038/s41467-020-16819-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305203PMC
June 2020
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