Sex and gender differences in lung health and disease are imperative to consider and study if precision pulmonary medicine is to be achieved. The development of reliable COPD biomarkers has been ...elusive, and the translation of biomarkers to clinical care has been limited. Useful and effective biomarkers must be developed with attention to clinical heterogeneity of COPD; inherent heterogeneity exists related to grouping women and men together in the studies of COPD. Considering sex and gender differences and influences related to -omics may represent progress in susceptibility, diagnostic, prognostic, and therapeutic biomarker development and clinical innovation to improve the lung health of men and women.
Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease ...progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.
Despite their known importance in clinical medicine, differences based on sex and gender are among the least studied factors affecting cancer susceptibility, progression, survival, and therapeutic ...response. In particular, the molecular mechanisms driving sex differences are poorly understood and so most approaches to precision medicine use mutational or other genomic data to assign therapy without considering how the sex of the individual might influence therapeutic efficacy. The mandate by the National Institutes of Health that research studies include sex as a biological variable has begun to expand our understanding on its importance. Sex differences in cancer may arise due to a combination of environmental, genetic, and epigenetic factors, as well as differences in gene regulation, and expression. Extensive sex differences occur genome-wide, and ultimately influence cancer biology and outcomes. In this review, we summarize the current state of knowledge about sex-specific genetic and genome-wide influences in cancer, describe how differences in response to environmental exposures and genetic and epigenetic alterations alter the trajectory of the disease, and provide insights into the importance of integrative analyses in understanding the interplay of sex and genomics in cancer. In particular, we will explore some of the emerging analytical approaches, such as the use of network methods, that are providing a deeper understanding of the drivers of differences based on sex and gender. Better understanding these complex factors and their interactions will improve cancer prevention, treatment, and outcomes for all individuals.
Sex differences manifest in many diseases and may drive sex-specific therapeutic responses. To understand the molecular basis of sex differences, we evaluated sex-biased gene regulation by ...constructing sample-specific gene regulatory networks in 29 human healthy tissues using 8,279 whole-genome expression profiles from the Genotype-Tissue Expression (GTEx) project. We find sex-biased regulatory network structures in each tissue. Even though most transcription factors (TFs) are not differentially expressed between males and females, many have sex-biased regulatory targeting patterns. In each tissue, genes that are differentially targeted by TFs between the sexes are enriched for tissue-related functions and diseases. In brain tissue, for example, genes associated with Parkinson’s disease and Alzheimer’s disease are targeted by different sets of TFs in each sex. Our systems-based analysis identifies a repertoire of TFs that play important roles in sex-specific architecture of gene regulatory networks, and it underlines sex-specific regulatory processes in both health and disease.
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•Sex differences are evident in sample-specific gene regulatory networks•TF sex-biased targeting of genes is independent of their differential expression•Sex-biased target genes are enriched for tissue-related functions and diseases•Rich public resource that includes 8,279 gene regulatory networks of 29 tissues
In analyzing 8,279 sample-specific gene regulatory networks, Lopes-Ramos et al. find significant sex differences in gene regulation across all 29 tissues analyzed. Transcription factors have sex-biased targeting patterns, and sex-biased target genes are associated with each tissue’s function and with diseases specific to that tissue.
The traditional view of chronic obstructive pulmonary disease (COPD) as a self-inflicted disease caused by tobacco smoking in genetically susceptible individuals has been challenged by recent ...research findings. COPD can instead be understood as the potential end result of the accumulation of gene-environment interactions encountered by an individual over the life course. Integration of a time axis in pathogenic models of COPD is necessary because the biological responses to and clinical consequences of different exposures might vary according to both the age of an individual at which a given gene-environment interaction occurs and the cumulative history of previous gene-environment interactions. Future research should aim to understand the effects of dynamic interactions between genes (G) and the environment (E) by integrating information from basic omics (eg, genomics, epigenomics, proteomics) and clinical omics (eg, phenomics, physiomics, radiomics) with exposures (the exposome) over time (T)-an approach that we refer to as GETomics. In the context of this approach, we argue that COPD should be viewed not as a single disease, but as a clinical syndrome characterised by a recognisable pattern of chronic symptoms and structural or functional impairments due to gene-environment interactions across the lifespan that influence normal lung development and ageing.
Growing evidence has linked positive psychological attributes like optimism to a lower risk of poor health outcomes, especially cardiovascular disease. It has been demonstrated in randomized trials ...that optimism can be learned. If associations between optimism and broader health outcomes are established, it may lead to novel interventions that improve public health and longevity. In the present study, we evaluated the association between optimism and cause-specific mortality in women after considering the role of potential confounding (sociodemographic characteristics, depression) and intermediary (health behaviors, health conditions) variables. We used prospective data from the Nurses' Health Study (n = 70,021). Dispositional optimism was measured in 2004; all-cause and cause-specific mortality rates were assessed from 2006 to 2012. Using Cox proportional hazard models, we found that a higher degree of optimism was associated with a lower mortality risk. After adjustment for sociodemographic confounders, compared with women in the lowest quartile of optimism, women in the highest quartile had a hazard ratio of 0.71 (95% confidence interval: 0.66, 0.76) for all-cause mortality. Adding health behaviors, health conditions, and depression attenuated but did not eliminate the associations (hazard ratio = 0.91, 95% confidence interval: 0.85, 0.97). Associations were maintained for various causes of death, including cancer, heart disease, stroke, respiratory disease, and infection. Given that optimism was associated with numerous causes of mortality, it may provide a valuable target for new research on strategies to improve health.
Modelling the regulatory mechanisms that determine cell fate, response to external perturbation, and disease state depends on measuring many factors, a task made more difficult by the plasticity of ...the epigenome. Scanning the genome for the sequence patterns defined by Position Weight Matrices (PWM) can be used to estimate transcription factor (TF) binding locations. However, this approach does not incorporate information regarding the epigenetic context necessary for TF binding. CpG methylation is an epigenetic mark influenced by environmental factors that is commonly assayed in human cohort studies. We developed a framework to score inferred TF binding locations using methylation data. We intersected motif locations identified using PWMs with methylation information captured in both whole-genome bisulfite sequencing and Illumina EPIC array data for six cell lines, scored motif locations based on these data, and compared with experimental data characterizing TF binding (ChIP-seq). We found that for most TFs, binding prediction improves using methylation-based scoring compared to standard PWM-scores. We also illustrate that our approach can be generalized to infer TF binding when methylation information is only proximally available,
. measured for nearby CpGs that do not directly overlap with a motif location. Overall, our approach provides a framework for inferring context-specific TF binding using methylation data. Importantly, the availability of DNA methylation data in existing patient populations provides an opportunity to use our approach to understand the impact of methylation on gene regulatory processes in the context of human disease.
Understanding sex differences in colon cancer is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than ...women. However, the molecular features that drive these sex differences are poorly understood. In this study, we use both transcript-based and gene regulatory network methods to analyze RNA-seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. We then inferred patient-specific gene regulatory networks and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset of 1,193 patients from five independent studies. While targeting, the drug metabolism pathway did not change overall survival for males treated with adjuvant chemotherapy, females with greater targeting showed an increase in 10-year overall survival probability, 89% 95% confidence interval (CI), 78-100 survival compared with 61% (95% CI, 45-82) for women with lower targeting, respectively (
= 0.034). Our network analysis uncovers patterns of transcriptional regulation that differentiate male and female colon cancer and identifies differences in regulatory processes involving the drug metabolism pathway associated with survival in women who receive adjuvant chemotherapy. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.
A network-based approach reveals that sex-specific patterns of gene targeting by transcriptional regulators are associated with survival outcome in colon cancer. This approach can be used to understand how sex influences progression and response to therapies in other cancers.
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The nasal cellular epigenome may serve as biomarker of airway disease and environmental response. Here we collect nasal swabs from the anterior nares of 547 children (mean-age 12.9 y), and measure ...DNA methylation (DNAm) with the Infinium MethylationEPIC BeadChip. We perform nasal Epigenome-Wide Association analyses (EWAS) of current asthma, allergen sensitization, allergic rhinitis, fractional exhaled nitric oxide (FeNO) and lung function. We find multiple differentially methylated CpGs (FDR < 0.05) and Regions (DMRs; ≥ 5-CpGs and FDR < 0.05) for asthma (285-CpGs), FeNO (8,372-CpGs; 191-DMRs), total IgE (3-CpGs; 3-DMRs), environment IgE (17-CpGs; 4-DMRs), allergic asthma (1,235-CpGs; 7-DMRs) and bronchodilator response (130-CpGs). Discovered DMRs annotated to genes implicated in allergic asthma, Th2 activation and eosinophilia (EPX, IL4, IL13) and genes previously associated with asthma and IgE in EWAS of blood (ACOT7, SLC25A25). Asthma, IgE and FeNO were associated with nasal epigenetic age acceleration. The nasal epigenome is a sensitive biomarker of asthma, allergy and airway inflammation.
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