Melanocortin-1 Receptor, Skin Cancer and Phenotypic Characteristics (M-SKIP) Project: Study Design and Methods for Pooling Results of Genetic Epidemiological Studies

Background: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. Design and methods: Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. Discussion: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields

Association between the BRCA2 N372H variant and male breast cancer risk: a population-based case-control study in Tuscany, Central Italy

Background: Male breast cancer (MBC) is a rare disease and little is known about its aetiology. Germline mutations of BRCA2 and, at lower frequency, of BRCA1 are implicated in a relatively small proportion of MBC cases. Common polymorphic variants in BRCA1 and BRCA2 genes may represent breast cancer (BC) susceptibility alleles and could be associated with a modestly increased risk of MBC at population level. Considering the relevant role of BRCA2 in MBC, we investigated whether the BRCA2 N372H variant, representing the only common non-synonymous polymorphism in BRCA2, might modulate the risk of BC in male populations.Methods: A case-control study was performed comparing a population-based series of 99 MBC cases, characterized for BRCA1 and BRCA2 mutations, with 261 male population controls, all residing in Tuscany, Central Italy. All MBC cases and controls were genotyped for the BRCA2 N372H allele by TaqMan allelic discrimination assays. To evaluate the genotype specific risk of the BRCA2 N372H variant, MBC carriers of germ-line BRCA1/2 mutations were excluded from the analyses.Results: No association emerged in univariate and age-adjusted analyses. Age-specific analyses suggested an increased risk for the HH homozygous genotype in subjects younger than 60 years. A statistically significant interaction emerged between this genotype and age (p = 0.032). When analyses were restricted to MBC cases enrolled in the first 4 years following diagnosis, a recessive model showed a significantly increased risk of MBC in HH subjects younger than 60 years (OR = 5.63; 95% CI = 1.70; 18.61).Conclusion: Overall, our findings, although based on a relatively small series, suggest that the BRCA2 HH homozygous genotype might be positively associated with an increased risk of MBC in men younger than 60 years

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Genome-wide expression profile of sporadic gastric cancers with microsatellite instability

Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response. © 2008 Elsevier Ltd. All rights reserved

Short-term exposure to ambient air pollution and individual emergency department visits for COVID-19:a case-crossover study in Canada

Abstract Background: Ambient air pollution is thought to contribute to increased risk of COVID-19, but the evidence is controversial. Objective: To evaluate the associations between short-term variations in outdoor concentrations of ambient air pollution and COVID-19 emergency department (ED) visits. Methods: We conducted a case-crossover study of 78 255 COVID-19 ED visits in Alberta and Ontario, Canada between 1 March 2020 and 31 March 2021. Daily air pollution data (ie, fine particulate matter with diameter less than 2.5 µm (PM2.5), nitrogen dioxide (NO₂) and ozone were assigned to individual case of COVID-19 in 10 km × 10 km grid resolution. Conditional logistic regression was used to estimate associations between air pollution and ED visits for COVID-19. Results: Cumulative ambient exposure over 0–3 days to PM2.5 (OR 1.010; 95% CI 1.004 to 1.015, per 6.2 µg/m³) and NO₂ (OR 1.021; 95% CI 1.015 to 1.028, per 7.7 ppb) concentrations were associated with ED visits for COVID-19. We found that the association between PM2.5 and COVID-19 ED visits was stronger among those hospitalised following an ED visit, as a measure of disease severity, (OR 1.023; 95% CI 1.015 to 1.031) compared with those not hospitalised (OR 0.992; 95% CI 0.980 to 1.004) (p value for effect modification=0.04). Conclusions: We found associations between short-term exposure to ambient air pollutants and COVID-19 ED visits. Exposure to air pollution may also lead to more severe COVID-19 disease

Evaluation of the ERA5 reanalysis-based Universal Thermal Climate Index on mortality data in Europe

Abstract Air temperature has been the most commonly used exposure metric in assessing relationships between thermal stress and mortality. Lack of the high-quality meteorological station data necessary to adequately characterize the thermal environment has been one of the main limitations for the use of more complex thermal indices. Global climate reanalyses may provide an ideal platform to overcome this limitation and define complex heat and cold stress conditions anywhere in the world. In this study, we explored the potential of the Universal Thermal Climate Index (UTCI) based on ERA5 – the latest global climate reanalysis from the European Centre for Medium-Range Weather Forecasts (ECMWF) – as a health-related tool. Employing a novel ERA5-based thermal comfort dataset ERA5-HEAT, we investigated the relationships between the UTCI and daily mortality data in 21 cities across 9 European countries. We used distributed lag nonlinear models to assess exposure-response relationships between mortality and thermal conditions in individual cities. We then employed meta-regression models to pool the results for each city into four groups according to climate zone. To evaluate the performance of ERA5-based UTCI, we compared its effects on mortality with those for the station-based UTCI data. In order to assess the additional effect of the UTCI, the performance of ERA5-and station-based air temperature (T) was evaluated. Whilst generally similar heat- and cold-effects were observed for the ERA5-and station-based data in most locations, the important role of wind in the UTCI appeared in the results. The largest difference between any two datasets was found in the Southern European group of cities, where the relative risk of mortality at the 1st percentile of daily mean temperature distribution (1.29 and 1.30 according to the ERA5 vs station data, respectively) considerably exceeded the one for the daily mean UTCI (1.19 vs 1.22). These differences were mainly due to the effect of wind in the cold tail of the UTCI distribution. The comparison of exposure-response relationships between ERA5-and station-based data shows that ERA5-based UTCI may be a useful tool for definition of life-threatening thermal conditions in locations where high-quality station data are not available

The BRCAPRO 5.0 model is a useful tool in genetic counseling and clinical management of male breast cancer cases

No study has evaluated the performance of BRCA1/2 mutations prediction models in male breast cancer (MBC) series. Although rare, MBC deserves attention because male and female breast cancers share many characteristics, including the involvement of genetic predisposition factors such as BRCA1/BRCA2 mutations. Indeed, the occurrence of MBC is a commonly used criterion to select families for BRCA mutation testing. We evaluated the performance and clinical effectiveness of four different predictive models in a population-based series of 102 Italian MBC patients characterized for BRCA1/2 mutations. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each risk model at the 10% threshold. The area under the ROC (AUC) curves and its corresponding asymptotic 95% CIs were calculated as a measure of the accuracy. In our study, the BRCAPRO version 5.0 had the highest combination of sensitivity, specificity, NPV and PPV for the combined probability and for the discrimination of BRCA2 mutations. In individuals with negative breast–ovarian cancer family history, BRCAPRO 5.0 reached a high discriminatory capacity (AUC=0.92) in predicting BRCA2 mutations and showed values of sensitivity, specificity, NPV and PPV of 0.5, 0.98, 0.97 and 0.67, respectively, for the combined probability. BRCAPRO version 5.0 can be particularly useful in dealing with non-familial MBC, a circumstance that often represents a challenging situation in genetic counseling

Circadian rhythm of COPD symptoms in clinically based phenotypes. Results from the STORICO Italian observational study

Background Chronic Obstructive Pulmonary Disease (COPD) encompasses various phenotypes that severely limit the applicability of precision respiratory medicine. The present investigation is aimed to assess the circadian rhythm of symptoms in pre-defined clinical COPD phenotypes and its association with health-related quality of life (HR-QoL), the quality of sleep and the level of depression/anxiety in each clinical phenotype. Methods The STORICO (NCT03105999) Italian observational prospective cohort study enrolled COPD subjects. A clinical diagnosis of either chronic bronchitis (CB), emphysema (EM) or mixed COPD-asthma (MCA) phenotype was made by clinicians at enrollment. Baseline early-morning, day-time and nocturnal symptoms (gathered via the Night-time, Morning and Day-time Symptoms of COPD questionnaire), HR-QoL (via the St. George's Respiratory Questionnaire), anxiety and depression levels (via the Hospital Anxiety and Depression Scale), quality of sleep (via COPD and Asthma Sleep Impact Scale), physical activity (via the International Physical Activity Questionnaire) as well as lung function were recorded. Results 606 COPD subjects (age 71.4 +/- 8.2 years, male 75.1%) were studied. 57.9, 35.5 5.3 and 1.3% of the sample belonged to the CB, EM, MCA and EM + CB phenotypes respectively. The vast majority of subjects reported early-morning and day-time symptoms (79.5 and 79.2% in the CB and 75.8 and 77.7% in the EM groups); the proportion suffering from night-time symptoms was higher in the CB than in the EM group (53.6% vs. 39.5%, p = 0.0016). In both CB and EM, indiscriminately, the presence of symptoms during the 24-h day was associated with poorer HR-QoL, worse quality of sleep and higher levels of anxiety/depression. Conclusions The findings highlight the primary classificatory role of nocturnal symptoms in COPD

Circadian rhythm of COPD symptoms in clinically based phenotypes. Results from the STORICO Italian observational study

Background: Chronic Obstructive Pulmonary Disease (COPD) encompasses various phenotypes that severely limit the applicability of precision respiratory medicine. The present investigation is aimed to assess the circadian rhythm of symptoms in pre-defined clinical COPD phenotypes and its association with health-related quality of life (HR-QoL), the quality of sleep and the level of depression/anxiety in each clinical phenotype. Methods: The STORICO (NCT03105999) Italian observational prospective cohort study enrolled COPD subjects. A clinical diagnosis of either chronic bronchitis (CB), emphysema (EM) or mixed COPD-asthma (MCA) phenotype was made by clinicians at enrollment. Baseline early-morning, day-time and nocturnal symptoms (gathered via the Night-time, Morning and Day-time Symptoms of COPD questionnaire), HR-QoL (via the St. George's Respiratory Questionnaire), anxiety and depression levels (via the Hospital Anxiety and Depression Scale), quality of sleep (via COPD and Asthma Sleep Impact Scale), physical activity (via the International Physical Activity Questionnaire) as well as lung function were recorded. Results: 606 COPD subjects (age 71.4 ± 8.2 years, male 75.1%) were studied. 57.9, 35.5 5.3 and 1.3% of the sample belonged to the CB, EM, MCA and EM + CB phenotypes respectively. The vast majority of subjects reported early-morning and day-time symptoms (79.5 and 79.2% in the CB and 75.8 and 77.7% in the EM groups); the proportion suffering from night-time symptoms was higher in the CB than in the EM group (53.6% vs. 39.5%, p = 0.0016). In both CB and EM, indiscriminately, the presence of symptoms during the 24-h day was associated with poorer HR-QoL, worse quality of sleep and higher levels of anxiety/depression. Conclusions: The findings highlight the primary classificatory role of nocturnal symptoms in COPD. Trial registration: Trial registration number: NCT03105999, date of registration: 10th April 2017