Exploring the Use of Omics to Eliminate Sex and Gender Differences in COPD

With substantial advances in the understanding of chronic obstructive pulmonary disease (COPD) in recent decades, it has become widely accepted that COPD encompasses a range of clinical phenotypes.¹ However, there have not been accompanying strides in the development of novel therapies tailored to the needs of various patient groups, which has hindered progress toward a precision medicine approach in COPD management.

The exploration of biomarker-based targeted treatment strategies for COPD would benefit exponentially from the use of large-scale “Omics” — namely, genomic, epigenomic, transcriptomic, proteomic, and metabolomic data. Realizing the true value of Omics in COPD research will require the recognition of observed sex and gender differences, noted Dawn L. DeMeo, MD, MPH, senior researcher and assistant professor of pulmonary and critical care medicine at Harvard Medical School in Boston, Massachusetts, and author of a review published online in March 2021 in CHEST.²

Numerous disparities have been noted between men and women with COPD. “We know that females vs males with the same smoking history are at increased risk of COPD, and they are more symptomatic and more likely to experience exacerbations; however, they are less likely to experience mortality,” explained Don D. Sin, MD, MPH, director and De Lazzari Family Chair at the Centre for Heart Lung Innovation (HLI), a Canada Research Chair in COPD, and professor in the Division of Respiratory Medicine at the University of British Columbia in Vancouver.^2,3

“In addition, female COPD patients tend to demonstrate greater airway disease and slightly less emphysema than male COPD patients,” Dr Sin told us in an interview.² Studies have also found sex-specific differential treatment effects in COPD. Inhaled therapies have shown greater effectiveness in women vs men, for example, and women who smoke may have more difficulty quitting compared with men who smoke.⁴

However, Omics analyses have largely failed to consider these differences in the search for COPD biomarkers. “One major barrier is that there is under-representation of females in COPD therapeutic trials and, as such, gender and sex effects have not been well explored,” said Dr Sin. “Further, there are very few discovery studies evaluating sex and gender effects in COPD. Thus, our knowledge about the mechanisms for the sex and gender effects are scant.”

Among the limited Omics studies that have considered these factors, selected results described in the CHEST review are summarized below.²

Genomics

While findings regarding sex-specific genetic risk factors for COPD have been mixed overall, a sex-stratified analysis in a 2017 genome-wide association study found that the SNP rs9615358 in the cadherin gene CELSR1 was linked to COPD in women (odds ratio [OR], 1.37; 95% CI, 1.25-1.49; P =3.32 × 10⁻⁷) but not men (OR, 0.90; 95% CI, 0.79-1.01; P =.06).⁵ 

This gene is “related to branching morphogenesis in the lung, suggesting that differences in airway development in males and females may set a lifelong trajectory of sex differences for susceptibility to COPD,” wrote Dr DeMeo.²

The investigators also observed significantly greater expression of CELSR1 in human fetal lung tissue from women vs men.⁵

Epigenomics

In epigenetic research, a small study found hundreds of sex-specific DNA methylation sites in fetal and adult lung tissue. A total of 3 cytosine-phosphate-guanine sites (GPR132, ANKRD44 and C19orf60) indicated a potential interaction between sex and pack-years of smoking, and effect estimates for men and women were in opposite directions.⁶

In other epigenetic findings, “differential methylation of sites in CYP1B1, a gene encoding a xenobiotic metabolizer, demonstrated association with reduced lung function and CT scan emphysema in females not males, suggesting larger scale investigations may reveal epigenetic biomarkers of smoke exposure portending COPD and associated phenotype risks.”²

Metabolomics and Proteomics

Metabolomic research has demonstrated dysregulation in the oxidative stress pathways, including the autotaxin-lysoPA axis, in women vs men with COPD.⁷

In proteomic analyses, greater dysregulation of phagocytotic pathways was observed in the lung cells of women with COPD, and this was correlated with lung function and emphysema.⁸ Results of other studies have shown elevated levels of adipokines and interleukin 16 in women with COPD as well as increased vascular endothelial growth factor levels in men with emphysema.²

“Circulating inflammatory proteins may represent important sex specific prognostic biomarkers; more attention put toward sex specific analysis of large scale proteomic and metabolomic platform data are warranted,” as stated in the review.²

Future Directions

Network-based approaches may enable integration of these various Omics findings to fully optimize the use of big data in identifying COPD biomarkers.²

Among the many remaining needs in these areas of study, including larger sample sizes and greater representation of women in COPD trials, the effect of gender-influenced exposures such as smoking behaviors and occupational exposures on sex differences in COPD should be closely examined.²

“Common approaches to pulmonary biomarker identification have not generally considered sex and gender as key organizing principles and all future biomarker studies should address these constructs,” Dr DeMeo concluded.² “Given that biomarkers may align with disease susceptibility, diagnosis, prognosis or therapeutic response and that there is ample data to support sex differences related to COPD, considering sex-specific biomarkers will facilitate the success of precision medicine for COPD for men and women.”

References

1. Leung JM, Obeidat M, Sadatsafavi M, Sin DD. Introduction to precision medicine in COPD. Eur Respir J. 2019;53(4):1802460. doi:10.1183/13993003.02460-2018

2. DeMeo DL. Sex and gender Omic biomarkers in men and women with COPD: considerations for precision medicine. Published online March 18, 2021. CHEST. doi:10.1016/j.chest.2021.03.024

3. Lisspers K, Larsson K, Janson C, et al. Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world retrospective cohort study. NPJ Prim Care Respir Med. 2019;29(1):45. doi:10.1038/s41533-019-0157-3

4. Li X, Obeidat M, Zhou G, et al. Responsiveness to ipratropium bromide in male and female patients with mild to moderate chronic obstructive pulmonary disease. EBioMedicine. 2017;19:139-145. doi:10.1016/j.ebiom.2017.04.020

5. Hardin M, Cho MH, Sharma S, et al; for the COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points Investigators. Sex-based genetic association study identifies CELSR1 as a possible chronic obstructive pulmonary disease risk locus among women. Am J Respir Cell Mol Biol. 2017;56(3):332-341. doi:10.1165/rcmb.2016-0172OC

6. Koo HK, Morrow J, Kachroo P, et al. Sex-specific associations with DNA methylation in lung tissue demonstrate smoking interactions. Epigenetics. 2020:1-12. doi:10.1080/15592294.2020.1819662

7. Naz S, Kolmert J, Yang M, Reinke SN, et al. Metabolomics analysis identifies sex-associated metabotypes of oxidative stress and the autotaxin-lysoPA axis in COPD. Eur Respir J. 2017;49(6):1602322. doi:10.1183/13993003.02322-2016

8. Yang M, Kohler M, Heyder T, et al. Proteomic profiling of lung immune cells reveals dysregulation of phagocytotic pathways in female-dominated molecular COPD phenotype. Respir Res. 2018;19(1):39. doi:10.1186/s12931-017-0699-2