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OBJECTIVE: Inhibitors of the interleukin 13 (IL-13) pathway, such as dupilumab, are licensed for atopic dermatitis and asthma. Adverse events resembling psoriatic disease after dupilumab initiation have been reported, but evidence is limited to case reports with uncertain causality. We aimed to investigate whether genetically mimicked IL-13 inhibition (IL-13i) is associated with risk of psoriatic arthritis (PsA) and psoriasis. METHODS: We instrumented IL-13i using a protein-coding variant in the IL13 gene, rs20541, that is associated with circulating eosinophil count (biomarker of IL-13i) at genome-wide significance in a study of 563,946 individuals. Outcome genetic data were taken from studies of PsA, psoriasis, and related spondyloarthritis traits in up to 10,588 cases and 209,287 controls. Colocalization analysis was performed to examine genetic confounding. We additionally used circulating IgE as a biomarker to test whether associations were replicated, both in the test and in an independent genetic dataset. We also replicated analyses using individual-level data from the UK Biobank. RESULTS: Genetically proxied IL-13i was associated with increased risk of PsA (odds ratio [OR] 37.39; 95% confidence interval [95% CI] 11.52-121.34; P = 1.64 × 10-9) and psoriasis (OR 20.08; 95% CI 4.38-92.01; P = 1.12 × 10-4). No consistent associations were found for Crohn disease, ulcerative colitis, ankylosing spondylitis, or iritis. Colocalization showed no strong evidence of genetic confounding for psoriatic disease. Results were replicated using circulating IgE for the exposure, using independent outcome data and using individual-level data. CONCLUSION: We provide supportive genetic evidence that IL-13i is linked to increased risk of PsA and psoriasis. Physicians prescribing IL-13 inhibitors should be vigilant for these adverse events.
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OBJECTIVES: Juvenile idiopathic arthritis (JIA)-associated uveitis (JIAU) is a serious JIA comorbidity that can result in vision impairment. This study aimed to identify genetic risk factors, within the major histocompatibility complex , for JIAU and evaluate their contribution for improving risk classification when combined with clinical risk factors. METHODS: Data on single nucleotide polymorphisms, amino acids and classical human leukocyte antigen (HLA) alleles were available for 2,497 JIA patients without uveitis and 579 JIAU patients (female=2060, male=1015). Analysis was restricted to patients with inferred European ancestry. Forward conditional logistic regression identified genetic markers exceeding a Bonferroni corrected significance (6x10-6). Multivariable logistic regression estimated the effects of clinical and genetic risk factors and a likelihood ratio test calculated the improvement in model fit when adding genetic factors. Uveitis risk classification performance of a model integrating genetic and clinical risk factors was estimated using area under the receiver operator characteristic curve and compared to a model of clinical risk factors alone. RESULTS: Three genetic risk factors were identified mapping to HLA-DRB1, HLA-DPB1 and HLA-A. These markers were statistically independent from clinical risk factors and significantly improved the fit of a model when included with clinical risk factors (P = 3.3x10-23). The addition of genetic markers improved the classification of JIAU compared to a model of clinical risk factors alone (AUC 0.75 vs. 0.71). CONCLUSIONS: Integration of a genetic and clinical risk prediction model outperforms a model based solely on clinical risk factors. Future JIAU risk prediction models should include genetic risk factors.
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OBJECTIVES: To compare the patterns of multimorbidity between people with and without rheumatic and musculoskeletal diseases (RMDs) and to describe how these patterns change by age and sex over time, between 2010 and 2019. PARTICIPANTS: 103 426 people with RMDs and 2.9 million comparators registered in 395 Wales general practices (GPs). Each patient with an RMD aged 0-100 years between January 2010 and December 2019 registered in Clinical Practice Research Welsh practices was matched with up to five comparators without an RMD, based on age, gender and GP code. PRIMARY OUTCOME MEASURES: The prevalence of 29 Elixhauser-defined comorbidities in people with RMDs and comparators categorised by age, gender and GP practices. Conditional logistic regression models were fitted to calculate differences (OR, 95% CI) in associations with comorbidities between cohorts. RESULTS: The most prevalent comorbidities were cardiovascular risk factors, hypertension and diabetes. Having an RMD diagnosis was associated with a significantly higher odds for many conditions including deficiency anaemia (OR 1.39, 95% CI (1.32 to 1.46)), hypothyroidism (OR 1.34, 95% CI (1.19 to 1.50)), pulmonary circulation disorders (OR 1.39, 95% CI 1.12 to 1.73) diabetes (OR 1.17, 95% CI (1.11 to 1.23)) and fluid and electrolyte disorders (OR 1.27, 95% CI (1.17 to 1.38)). RMDs have a higher proportion of multimorbidity (two or more conditions in addition to the RMD) compared with non-RMD group (81% and 73%, respectively in 2019) and the mean number of comorbidities was higher in women from the age of 25 and 50 in men than in non-RMDs group. CONCLUSION: People with RMDs are approximately 1.5 times as likely to have multimorbidity as the general population and provide a high-risk group for targeted intervention studies. The individuals with RMDs experience a greater load of coexisting health conditions, which tend to manifest at earlier ages. This phenomenon is particularly pronounced among women. Additionally, there is an under-reporting of comorbidities in individuals with RMDs.
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Registros Electrónicos de Salud , Multimorbilidad , Enfermedades Musculoesqueléticas , Enfermedades Reumáticas , Humanos , Femenino , Masculino , Enfermedades Musculoesqueléticas/epidemiología , Persona de Mediana Edad , Gales/epidemiología , Adulto , Anciano , Enfermedades Reumáticas/epidemiología , Registros Electrónicos de Salud/estadística & datos numéricos , Adolescente , Adulto Joven , Niño , Anciano de 80 o más Años , Preescolar , Lactante , Prevalencia , Recién Nacido , Estudios de Cohortes , Factores de RiesgoRESUMEN
OBJECTIVE: First Nations children face a greater risk of experiencing mental disorders than other children from the general population because of family and societal factors, yet there is little research examining their mental health. This study compares diagnosed mental disorders and suicidal behaviours of First Nations children living on-reserve and off-reserve to all other children living in Manitoba. METHOD: The research team, which included First Nations and non-First Nations researchers, utilized population-based administrative data that linked de-identified individual-level records from the 2016 First Nations Research File to health and social information for children living in Manitoba. Adjusted rates and rate ratios of mental disorders and suicide behaviours were calculated using a generalized linear modelling approach to compare First Nations children (n = 40,574) and all other children (n = 197,109) and comparing First Nations children living on- and off-reserve. RESULTS: Compared with all other children, First Nations children had a higher prevalence of schizophrenia (adjusted rate ratio (aRR): 4.42, 95% confidence interval (CI), 3.36 to 5.82), attention-deficit hyperactivity disorder (ADHD; aRR: 1.21, 95% CI, 1.09 to 1.33), substance use disorders (aRR: 5.19; 95% CI, 4.25 to 6.33), hospitalizations for suicide attempts (aRR: 6.96; 95% CI, 4.36 to 11.13) and suicide deaths (aRR: 10.63; 95% CI, 7.08 to 15.95). The prevalence of ADHD and mood/anxiety disorders was significantly higher for First Nations children living off-reserve compared with on-reserve; in contrast, hospitalization rates for suicide attempts were twice as high on-reserve than off-reserve. When the comparison cohort was restricted to only other children in low-income areas, a higher prevalence of almost all disorders remained for First Nations children. CONCLUSION: Large disparities were found in mental health indicators between First Nations children and other children in Manitoba, demonstrating that considerable work is required to improve the mental well-being of First Nations children. Equitable access to culturally safe services is urgently needed and these services should be self-determined, planned, and implemented by First Nations people.
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Trastornos Mentales , Humanos , Manitoba/epidemiología , Femenino , Niño , Masculino , Adolescente , Estudios Retrospectivos , Trastornos Mentales/epidemiología , Intento de Suicidio/estadística & datos numéricos , Indígena Canadiense/estadística & datos numéricos , Preescolar , Prevalencia , Indígenas Norteamericanos/estadística & datos numéricosRESUMEN
Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.
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Enfermedades Autoinmunes , Polimorfismo de Nucleótido Simple , Humanos , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad/genética , Enfermedades Autoinmunes/genética , Regiones Promotoras Genéticas/genética , Aminopeptidasas/genéticaRESUMEN
TRAF1/C5 was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using Immunochip data from 3,939 patients with juvenile idiopathic arthritis (JIA) and 14,412 control individuals, we identified 132 plausible common non-coding variants, reduced serially by single-nucleotide polymorphism sequencing (SNP-seq), electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron of TRAF1. Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-related antigen 2 (FRA2), encoded by FOSL2, resulting in reduced TRAF1 expression and enhanced tumor necrosis factor (TNF) production. Conditioning on this JIA variant eliminated attributable risk for rheumatoid arthritis, implicating a mechanism shared across the arthritis spectrum. These findings reveal that rs7034653, FRA2, and TRAF1 mediate a pathway through which a non-coding functional variant drives risk of inflammatory arthritis in children and adults.
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OBJECTIVE: There is growing evidence that genetic data are of benefit in the rheumatology outpatient setting by aiding early diagnosis. A genetic probability tool (G-PROB) has been developed to aid diagnosis has not yet been tested in a real-world setting. Our aim was to assess whether G-PROB could aid diagnosis in the rheumatology outpatient setting using data from the Norfolk Arthritis Register (NOAR), a prospective observational cohort of patients presenting with early inflammatory arthritis. METHODS: Genotypes and clinician diagnoses were obtained from patients from NOAR. Six G-probabilities (0%-100%) were created for each patient based on known disease-associated odds ratios of published genetic risk variants, each corresponding to one disease of rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, spondyloarthropathy, gout, or "other diseases." Performance of the G-probabilities compared with clinician diagnosis was assessed. RESULTS: We tested G-PROB on 1,047 patients. Calibration of G-probabilities with clinician diagnosis was high, with regression coefficients of 1.047, where 1.00 is ideal. G-probabilities discriminated clinician diagnosis with pooled areas under the curve (95% confidence interval) of 0.85 (0.84-0.86). G-probabilities <5% corresponded to a negative predictive value of 96.0%, for which it was possible to suggest >2 unlikely diseases for 94% of patients and >3 for 53.7% of patients. G-probabilities >50% corresponded to a positive predictive value of 70.4%. In 55.7% of patients, the disease with the highest G-probability corresponded to clinician diagnosis. CONCLUSION: G-PROB converts complex genetic information into meaningful and interpretable conditional probabilities, which may be especially helpful at eliminating unlikely diagnoses in the rheumatology outpatient setting.
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Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.
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PURPOSE: Approximately 30% of patients with psoriasis will develop psoriatic arthritis (PsA), leading to a decreased quality of life for the patient caused by increasing disability and additional health complications. The identification of risk factors for the development of PsA would facilitate the development of risk prediction models in which patients with psoriasis at high risk of developing PsA could be targeted in a stratified medicine approach, enabling early intervention and treatment. PsA is known to have a genetic contribution to susceptibility, and the identification of genetic risk factors that differentiate PsA from cutaneous-only psoriasis is a key area of research. This narrative review summarizes the discovery of genetic risk factors and, with the aid of a primer on risk prediction models, discusses their potential role for the classification of PsA risk and diagnosis. METHODS: All relevant research articles were identified through searches of the PubMed database for literature published up until December 2022. Search terms included psoriatic arthritis, genetic susceptibility, genetic association, genome-wide association study, GWAS, prediction, and polygenic risk score. FINDINGS: The current literature reveals considerable overlap between the genetic susceptibility loci for PsA and psoriasis. Several PsA-specific genetic risk factors have been reported, and most notably these implicate the HLA-B and IL23R genes. Efforts to include genetic risk factors in prediction models for the development of PsA have reported good discrimination. IMPLICATIONS: Key messages emerging from this narrative are as follows: the limited number of PsA-specific susceptibility loci reported to date suggest larger studies are required, facilitated by international collaboration, to achieve the power to detect further genetic factors; the early promising results for genetic-based risk prediction require further validation in independent datasets; and risk prediction models combining clinical and genetic risk factors have yet to be explored.
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Artritis Psoriásica , Psoriasis , Humanos , Artritis Psoriásica/genética , Estudio de Asociación del Genoma Completo , Calidad de Vida , Psoriasis/genética , Predisposición Genética a la EnfermedadRESUMEN
PURPOSE: Screening with low-dose computed tomography reduces lung cancer (LC) mortality. Risk prediction models used for screening selection do not include genetic variables. Here, we investigated the performance of previously published polygenic risk scores (PRSs) for LC, considering their potential to improve screening selection. METHODS: We validated 9 PRSs in a high-risk case-control cohort, comprising genotype data from 652 surgical patients with LC and 550 cancer-free, high-risk (PLCOM2012 score ≥ 1.51%) participants of the Manchester Lung Health Check, a community-based LC screening program (n = 550). Discrimination (area under the curve [AUC]) between cases and controls was assessed for each PRS independently and alongside clinical risk factors. RESULTS: Median age was 67 years, 53% were female, 46% were current smokers, and 76% were National Lung Screening Trial eligible. Median PLCOM2012 score among controls was 3.4%, 80% of cases were early stage. All PRSs significantly improved discrimination, AUC increased between +0.002 (P = .02) and +0.015 (P < .0001), compared with clinical risk factors alone. The best-performing PRS had an independent AUC of 0.59. Two novel loci, in the DAPK1 and MAGI2 genes, were significantly associated with LC risk. CONCLUSION: PRSs may improve LC risk prediction and screening selection. Further research, particularly examining clinical utility and cost-effectiveness, is required.
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Neoplasias Pulmonares , Humanos , Femenino , Anciano , Masculino , Medición de Riesgo/métodos , Factores de Riesgo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Genotipo , Estudios de Casos y ControlesRESUMEN
PURPOSE: A third of familial epithelial ovarian cancer (EOC) is explained by BRCA1/2 pathogenic variants. Polygenic risk scores (PRSs) for BRCA1/2 heterozygotes associated with EOC have been created, but impact of combination with clinical and hormonal risk factors is unclear. METHODS: We genotyped 300 cases and 355 controls and constructed modified PRSs based on those validated by Barnes et al. Model discrimination and EOC risk was assessed by area under the curve (AUC) values and difference between lowest and highest quintile odds ratios (ORs). We investigated model optimization using logistic regression to combine models with clinical and hormonal data. RESULTS: Unadjusted AUC values ranged from 0.526 to 0.551 with 2.2- to 2.3-fold increase in OR between lowest and highest quintiles (BRCA1 heterozygotes) and 0.574 to 0.585 AUC values with a 6.3- to 7.7-fold increase (BRCA2 heterozygotes). The optimized model (parity, age at menarche, menopause, and first full-term pregnancy) estimated AUC values of 0.872 to 0.876 and 21- to 23-fold increase in OR (BRCA1 heterozygotes) and AUC values of 0.857 to 0.867 and 40- to 41-fold increase (BRCA2 heterozygotes). CONCLUSION: The combination of PRS with age, family history, and hormonal factors significantly improved the EOC risk discrimination ability. However, the contribution of the PRS was small. Larger prospective studies are needed to assess if combined-PRS models could provide information to inform risk-reducing decisions.
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Neoplasias de la Mama , Neoplasias Ováricas , Embarazo , Humanos , Femenino , Proteína BRCA1/genética , Heterocigoto , Carcinoma Epitelial de Ovario/genética , Predisposición Genética a la Enfermedad , Proteína BRCA2/genética , Factores de Riesgo , Neoplasias Ováricas/genéticaRESUMEN
During the COVID-19 pandemic, new parents were disproportionately affected by public health restrictions changing service accessibility and increasing stressors. However, minimal research has examined pandemic-related stressors and experiences of perinatal fathers in naturalistic anonymous settings. An important and novel way parents seek connection and information is through online forums, which increased during COVID-19. The current study qualitatively analyzed the experiences of perinatal fathers from September to December 2020 through the Framework Analytic Approach to identify unmet support needs during COVID-19 using the online forum predaddit on reddit. Five main themes in the thematic framework included forum use, COVID-19, psychosocial distress, family functioning, and child health and development, each with related subthemes. Findings highlight the utility of predaddit as a source of information for, and interactions of, fathers to inform mental health services. Overall, fathers used the forum to engage with other fathers during a time of social isolation and for support during the transition to parenthood. This manuscript highlights the unmet support needs of fathers during the perinatal period and the importance of including fathers in perinatal care, implementing routine perinatal mood screening for both parents, and developing programs to support fathers during this transition to promote family wellbeing.
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COVID-19 , Servicios de Salud Mental , Masculino , Embarazo , Femenino , Niño , Humanos , Pandemias , Padre/psicología , Parto/psicologíaRESUMEN
The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
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Síndrome de Behçet , Espondiloartritis , Uveítis , Humanos , Predisposición Genética a la Enfermedad , Síndrome de Behçet/genética , Antígenos de Histocompatibilidad Clase I/genética , Aminopeptidasas/genética , Antígenos de Histocompatibilidad Menor/genéticaRESUMEN
Importance: Lipid pathways have been implicated in the pathogenesis of psoriasis, and some lipid-lowering drugs, such as statins, are hypothesized to have disease-modifying properties. However, large population-level studies are scarce, and causal interpretation of results from traditional observational designs is limited by confounding. Objective: To investigate the causal association between genetically proxied lipid-lowering drugs and psoriasis risk. Design, Setting, and Participants: This 2-sample mendelian randomization study was performed from August to October 2022 and included population-level genome-wide association studies of psoriasis in the UK Biobank and FinnGen studies and low-density lipoprotein (LDL) by the Global Lipids Genetics Consortium. The inverse variance-weighted method was used with pleiotropy robust methods and colocalization as sensitivity analyses. Exposures: Genetically proxied inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR, targeted by statins), Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by, eg, alirocumab), using LDL as the biomarker. Main Outcomes and Measures: Risk of psoriasis. Results: Data from 12â¯116 patients with psoriasis and approximately 1.3 million individuals with LDL measurement were analyzed. Genetically proxied PCSK9 inhibition was associated with reduced risk of psoriasis (odds ratio, 0.69 per standard deviation reduction in LDL; 95% CI, 0.55-0.88; P = .003), which was replicated in FinnGen (odds ratio, 0.71; 95% CI, 0.57-0.88; P = .002). Sensitivity analyses did not provide statistical evidence of bias from pleiotropy or genetic confounding. No robust association was found for HMGCR or NPC1L1 inhibition. Conclusions and Relevance: This mendelian randomization study suggests that PCSK9 is implicated in psoriasis pathogenesis, and its inhibition is associated with reduced psoriasis risk. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of psoriasis.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Proproteína Convertasa 9/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , LípidosRESUMEN
OBJECTIVES: To examine associations between PsA and psoriasis vs lifestyle factors and comorbidities by triangulating observational and genetic evidence. METHODS: We analysed cross-sectional data from the UK Biobank (1836 PsA, 8995 psoriasis, 36 000 controls) to describe the association between psoriatic disease and lifestyle factors (including BMI and smoking) and 15 comorbidities [including diabetes and coronary artery disease (CAD)] using logistic models adjusted for age, sex and lifestyle factors. We applied bidirectional Mendelian randomization (MR) to genome-wide association data (3609 PsA and 7804 psoriasis cases, up to 1.2 million individuals for lifestyle factors and 757â601 for comorbidities) to examine causal direction, using the inverse-variance weighted method. RESULTS: BMI was cross-sectionally associated with risk of PsA (OR 1.31 per 5 kg/m2 increase; 95% CI 1.26, 1.37) and psoriasis (OR 1.23; 1.20, 1.26), with consistent MR estimates (PsA OR 1.38; 1.14, 1.67; psoriasis OR 1.36; 1.18, 1.58). In both designs, smoking was more strongly associated with psoriasis than PsA. PsA and psoriasis were cross-sectionally associated with diabetes (OR 1.35 and 1.39, respectively) and CAD (OR 1.56 and 1.38, respective). Genetically predicted glycated haemoglobin (surrogate for diabetes) increased PsA risk (OR 1.18 per 6.7 mmol/mol increase; 1.02, 1.36) but not psoriasis. Genetic liability to PsA (OR 1.05; 1.003, 1.09) and psoriasis (OR 1.03; 1.001, 1.06) were associated with increased risk of CAD. CONCLUSION: Observational and genetic evidence converge to suggest that BMI and glycaemic control are associated with increased psoriatic disease risk, while psoriatic disease is associated with increased CAD risk. Further research is needed to understand the mechanism of these associations.
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Artritis Psoriásica , Enfermedad de la Arteria Coronaria , Diabetes Mellitus , Psoriasis , Humanos , Artritis Psoriásica/complicaciones , Estudios Transversales , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Psoriasis/complicaciones , Estilo de VidaRESUMEN
Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants. To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10-13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.
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Neurilemoma , Neurofibromatosis , Neurofibromatosis 2 , Neuroma Acústico , Neoplasias Cutáneas , Humanos , Neuroma Acústico/genética , Estudio de Asociación del Genoma Completo , Neurilemoma/genética , Neurilemoma/patología , Neurofibromatosis/genética , Neoplasias Cutáneas/genética , Neurofibromatosis 2/genética , Factores de Transcripción/genéticaRESUMEN
Background: The healthcare system in Manitoba, Canada has faced long wait times for many surgical procedures and investigations, including orthopedic and ophthalmology surgeries. Wait times for surgical procedures is considered a significant barrier to accessing healthcare in Canada and can have negative health outcomes for patients. We developed models to forecast anticipated surgical procedure demands up to 2027. This paper explores the opportunities and challenges of using administrative data to describe forecasts of surgical service delivery. Methods: This study used whole population linked administrative health data to predict future orthopedic and ophthalmology surgical procedure demands up to 2027. Procedure codes (CCI) from hospital discharge abstracts and medical claims data were used in the modelling. A Seasonal Autoregressive Integrated Moving Average model provided the best fit to the data from April 1, 2004 to March 31, 2020. Results: Initial analyses of only hospital-based procedures excluded a significant portion of provider workload, namely those services provided in clinics. We identified 500,732 orthopedic procedures completed between April 1, 2004 and March 31, 2020 (349,171 procedures identified from hospital discharge abstracts and 151,561 procedures from medical claims). Procedure volumes for these services are expected to rise 17.7% from 2020 (36,542) to 2027 (43,011), including the forecasted 43.9% increase in clinic-based procedures. Of the 660,127 ophthalmology procedures completed between April 1, 2004 and March 31, 2020, 230,717 procedures were identified from hospital discharge abstracts and 429,410 from medical claims. Models forecasted a 27.7% increase from 2020 (69,598) to 2027 (88,893) with most procedures being performed in clinics. Conclusion: Researchers should consider including multiple datasets to add information that may have been missing from the presumed data source in their research approach. Confirming the completeness of the data is critical in modelling accurate predictions. Forecast modelling techniques have evolved but still require validation.