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.

Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported. Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45–80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering. The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter’s syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative “COPD-subtype”, “Restrictive-subtype”, and a highly symptomatic “Metabolic-subtype”. PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted. Clinicaltrials.gov Identifier: NCT000608764 .

Background The number of female smokers developing chronic obstructive pulmonary disease (COPD) is rapidly increasing, but whether or not there exists a differential susceptibility by gender remains controversial. Methods How smoking behaviour and subsequent lung function reduction differed by gender was examined in a study including 954 subjects with COPD and 955 subjects without COPD. The study focused on two subgroups: subjects with COPD <60 years of age (early-onset group, n=316) and subjects with COPD with <20 pack-years of smoking (low exposure group, n=241). Results In the low exposure group, female subjects with COPD had lower forced expiratory volume in 1 s (FEV₁) % predicted (48.7% vs 55.8%, p=0.001) and more severe disease (50.4% vs 35.6%, p=0.020, in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 3 and 4) than male subjects with COPD. Females also had lower FEV₁% predicted (50.6% vs 56.0%, p=0.006) and more severe COPD (41.7% vs 31.1% in GOLD stage 3 and 4, p=0.050) in the early-onset group. Using multivariate regression, female gender was associated with 5.7% lower FEV₁% predicted in the low exposure group (p=0.012) and a similar trend was observed in the early-onset group (p=0.057). The number of pack-years was not significantly associated with lung function in female subjects with COPD in this study, and the dose–response relationship between smoking and lung function differed by gender at lower levels of smoking exposure. Interaction analysis suggested that the effect of smoking on lung function might be different by gender (p=0.027 in all subjects with COPD). Conclusions Female gender was associated with lung function reduction and more severe disease in subjects with COPD with early onset of disease or low smoking exposure. The findings may suggest a gender difference in susceptibility to the lung-damaging effects of cigarette smoking, but alternative explanations should be considered.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with local (lung) and systemic (blood) inflammation and manifestations. DNA methylation is an important regulator of gene transcription, and global and specific gene methylation marks may vary with cigarette smoke exposure. Objectives: To perform a comprehensive assessment of methylation marks in DNA from subjects well phenotyped for nonneoplastic lung disease. Methods: We conducted array-based methylation screens, using a test-replication approach, in two family-based cohorts (n = 1,085 and 369 subjects). Measurements and Main Results: We observed 349 CpG sites significantly associated with the presence and severity of COPD in both cohorts. Seventy percent of the associated CpG sites were outside of CpG islands, with the majority of CpG sites relatively hypomethylated. Gene ontology analysis based on these 349 CpGs (330 genes) suggested the involvement of a number of genes responsible for immune and inflammatory system pathways, responses to stress and external stimuli, as well as wound healing and coagulation cascades. Interestingly, our observations include significant, replicable associations between SERPINA1 hypomethylation and COPD and lower average lung function phenotypes (combined P values: COPD, 1.5 × 10−23; FEV1/FVC, 1.5 × 10−35; FEV1, 2.2 × 10−40). Conclusions: Genetic and epigenetic pathways may both contribute to COPD. Many of the top associations between COPD and DNA methylation occur in biologically plausible pathways. This large-scale analysis suggests that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis.

Rationale: The characterization of young adults who develop late-onset diseases may augment the detection of novel genes and promote new pathogenic insights. Methods: We analyzed data from 2,500 individuals of African and European ancestry in the COPDGene Study. Subjects with severe, early-onset chronic obstructive pulmonary disease (COPD) (n = 70, age < 55 yr, FEV₁ < 50% predicted) were compared with older subjects with COPD (n = 306, age > 64 yr, FEV₁ < 50% predicted). Measurements and Main Results: Subjects with severe, early-onset COPD were predominantly females (66%), P = 0.0004. Proportionally, early-onset COPD was seen in 42% (25 of 59) of African Americans versus 14% (45 of 317) of non-Hispanic whites, P < 0.0001. Other risk factors included current smoking (56 vs. 17%, P < 0.0001) and self-report of asthma (39 vs. 25%, P = 0.008). Maternal smoking (70 vs. 44%, P = 0.0001) and maternal COPD (23 vs. 12%, P = 0.03) were reported more commonly in subjects with early-onset COPD. Multivariable regression analysis found association with African American race, odds ratio (OR), 7.5 (95% confidence interval [CI], 2.3–24; P = 0.0007); maternal COPD, OR, 4.7 (95% CI, 1.3–17; P = 0.02); female sex, OR, 3.1 (95% CI, 1.1–8.7; P = 0.03); and each pack-year of smoking, OR, 0.98 (95% CI, 0.96–1.0; P = 0.03). Conclusions: These observations support the hypothesis that severe, early-onset COPD is prevalent in females and is influenced by maternal factors. Future genetic studies should evaluate (1) gene-by-sex interactions to address sex-specific genetic contributions and (2) gene-by-race interactions.

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.