The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, ...a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.
The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.
None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.
Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.
There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, ...the interplay between such risk factors and susceptibility loci has not been studied.
Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic "risk score" was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk.
Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest 95% confidence interval (CI), 1.48-1.84. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet < 0.001), parity (Phet < 0.01), and tubal ligation (Phet = 0.041).
The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted.
Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the ...different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.
We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.
Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant.
Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.
Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression ...signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.
Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.
Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001. Median survival HR (95% CI) by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years.
The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
•A gene expression signature for high-grade serous ovarian cancer prognostic for 2- and 5-year overall survival (OS).•The 101 gene expression signature performs substantially better than age and stage alone.•Median survival by quintile was 9.5, 5.4, 3.8, 3.2 and 2.3 years.•The top five genes associated with OS were TAP1, ZFHX4, CXCL9, FBN1, and PTGER3 (P < 0.001).
Objective
To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout.
...Methods
A 19‐variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex‐stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease.
Results
The PRS was associated with earlier age at gout onset in men (β = –3.61 in years per unit PRS 95% confidence interval (95% CI) –4.32, –2.90 in European men; β = –6.35 95% CI –8.91, –3.80 in East Polynesian men; β = –3.51 95% CI –5.46, –1.57 in West Polynesian men) but not in women (β = 0.07 95% CI –2.32, 2.45 in European women; β = 0.20 95% CI –7.21, 7.62 in East Polynesian women; β –3.33 95% CI –9.28, 2.62 in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio OR for the association 1.15 95% CI 1.00, 1.31 in European men; OR 2.60 95% CI 1.66, 4.06 in East Polynesian men; OR 1.53 95% CI 1.07, 2.19 in West Polynesian men) but not in women (OR for the association 0.68 95% CI 0.42, 1.10 in European women; OR 1.45 95% CI 0.39, 5.36 in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (β = –2.42 95% CI –3.37, –1.46 and β = –6.80 95% CI –10.06, –3.55, respectively) but not in West Polynesian men (β = –1.79 95% CI –4.74, 1.16).
Conclusion
Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.
House cats Felis catus have contributed to the extinction of many bird species on islands, but their impact on continental bird faunas is less well resolved. Here, we compile and analyse a ...comprehensive record of all bird species known to be killed by feral cats at a continental scale. From published studies and unpublished data, we document predation by feral and pet cats on 357 bird species in Australia, including 338 Australian (non-vagrant) native bird species (=45.6% of the 741 Australian native bird species, excluding vagrants). This tally included 24 species listed as threatened or extinct by the IUCN (40% of the 58 non-vagrant Australian species listed as threatened), and 71 of the 117 bird species (61%) listed as threatened under Australian legislation (or species with one or more subspecies so listed). These tallies are substantially larger than reported in previous reviews. We provide the first continental-scale attempt to model bird species' traits that are associated with likelihood of being killed by cats, and use such modelling to attempt to redress some inevitable biases in compilation of predation records on birds. We conclude that the likelihood of being killed by a cat was highest for bird species that are restricted to islands, are of intermediate body mass (ca. 60–300g), and nest and forage on the ground, and least likely for bird species occurring mostly in rainforests and wetlands. We also identify a set of bird species most likely to be threatened by cat-predation and hence most likely to benefit from enhanced management of cats. This study does not specifically evaluate the impact of cats on bird populations or on the conservation of Australian birds, but our results suggest that such impact may be much more pervasive than previously documented.
There is a growing need to understand the inter-annual movements of mobile marine species of conservation concern to inform the design and placement of Marine Protected Areas (MPAs) to maximise their ...conservation potential. We use satellite telemetry data from 36 basking sharks (Cetorhinus maximus) tracked in 2012, 2013 and 2014 (cumulative total: 1598days; median: 44days; range: 10–87days) to quantify movements in coastal waters off the west coast of Scotland within the Sea of the Hebrides proposed MPA. Sharks exhibited seasonal residency to the proposed MPA, with a mean of 84% of filtered best daily locations occurring within its boundaries (2012=80%, 2013=90% and 2014=74%). Three long-term tracked basking sharks demonstrated inter-annual site fidelity, returning to the same coastal waters in the year following tag deployment, with two returning to within the boundaries of the proposed MPA. These data likely suggest the area experiences favourable conditions and/or resources for basking sharks across years and, if designated, coupled with appropriate management, could afford protection during summer months.
•Testing of a MPA prior to designation, a process not often afforded to most MPAs•High levels of residency, with >90% overlap between core activity areas and the MPA•Inter-annual site fidelity of individuals to the area, showing year-round migration•Study area likely provides conditions for key life history events to occur
Background
Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models ...can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis.
Methods
A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis).
Results
Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent).
Conclusion
Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified.
Antecedentes
La apendicitis es la urgencia quirúrgica de cirugía general más frecuente en todo el mundo, pero su diagnóstico sigue siendo un desafío. El objetivo de este estudio fue determinar si los modelos de predicción de riesgo existentes pueden identificar de manera fiable a los pacientes del Reino Unido que se presentan en el hospital con dolor agudo en la fosa ilíaca derecha (right iliac fossa, RIF) con bajo riesgo de apendicitis.
Métodos
Se realizó una búsqueda sistemática para identificar todos los modelos existentes de predicción de riesgo de apendicitis. Los modelos se validaron utilizando los datos del Reino Unido de un estudio International prospectivo de cohortes que incluía pacientes consecutivos de 16 a 45 años que se presentaron en el hospital con dolor agudo en RIF entre marzo y junio de 2017. El criterio de valoración principal fue la mejor especificidad que era posible alcanzar con el modelo (proporción de pacientes que no tenían apendicitis correctamente clasificados como de bajo riesgo) manteniendo una tasa de fracaso < 5% (proporción de pacientes identificados como de bajo riesgo que realmente tuvieron apendicitis).
Resultados
Se identificaron 5.345 pacientes en 154 hospitales del Reino Unido, de los cuales dos tercios (67,6%, 3.613/5.345) eran mujeres. Las mujeres tenían más del doble de probabilidades de someterse a una apendicectomía con un apéndice histológicamente normal (28,2%; 272/964) en comparación con los varones (12,1%; 120/993, riesgo relativo 2,33 (i.c. del 95% 1,92‐2,84), P < 0,001)). Entre los 15 modelos de predicción de riesgo validados, el sistema de puntuación de apendicitis en adultos (Adult Appendicitis Score) fue el que obtuvo la mejor predicción (punto de corte ≤ 8, especificidad 63%, tasa de fracaso 3,7%). El sistema de puntuación de la respuesta inflamatoria de apendicitis (Appendicitis Inflammatory Response Score) fue el que obtuvo la mejor predicción en los varones (punto de corte ≤ 2, especificidad 25%, tasa de fracaso 2,4%).
Conclusión
Las mujeres del Reino Unido tuvieron un riesgo desproporcionado de ingreso sin intervención quirúrgica, así como porcentajes elevados de apendicectomías blancas. Se encontraron modelos de predicción de riesgos para apoyar la toma de decisiones compartida mediante la identificación de adultos del Reino Unido con bajo riesgo de apendicitis.
Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making were identified by identifying UK adults at low risk of appendicitis. An online calculator is available (http://appy‐risk.org). WCC, white cell count; CRP, C‐reactive protein; AIRS, Appendicitis Inflammatory Response Score; AAS, Adult Appendicitis Score.
Important differences between men and women
Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide ...universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention.
MHC class I molecules present peptides generated by processing of endogenously synthesized proteins to CD8
+ T lymphocytes. Recently, large proteolytic complexes, termed proteasomes, were implicated ...in antigen processing. Two proteasomal subunits, LMP2 and LMP7, are encoded within the MHC class II region, but their precise role in antigen processing is unknown. We have generated mice that harbor a disruption in their
LMP2 gene. Proteasomes purified from spleen and liver of these mutant mice exhibit altered peptidase activities, and antigen-presenting cells showed reduced capacity to stimulate a T cell hybridoma specific for H-2D
b plus a nucleoprotein epitope of an influenza A virus. The mutant mice have reduced (60%–70% of wild type) levels of CD8
+ T lymphocytes and generate 5- to 6-fold fewer influenza nucleoprotein-specific cytotoxic T lymphocyte precursors. These findings indicate that LMP2 influences antigen processing.
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