Chronic Sinusitis: Genes Or Environment?

Devyani Lal, MD, and Naweed Chowdhury, MD, MPH, on behalf of the Rhinology and Allergy Education Committee

Unfavorable environmental assaults on the sinus mucosa, including infection, microbial dysbiosis, allergens, and air pollution, in susceptible hosts are currently thought to trigger the abnormal immune response that leads to chronic rhinosinusitis (CRS).¹ Recently, there has been more interest in genetic susceptibility as a CRS risk factor, particularly given that many of these environmental factors are ubiquitous in a region, yet only a subset of people develop disease.

Although familial clustering has long been reported in CRS patients, the genetic architecture of this disease remains poorly understood.² For example, Bohman et al.³ found that the prevalence of CRSwNP in relatives was 13.4% versus 2.7% in controls; a relative risk of 4.9 in the first-degree relatives in the Swedish population. However, monogenic mutations have not been identified in most CRS patients.^2,4–6 It is thought that CRS clustering might be polygenic with contributions from alterations in expression of various genes. In addition, familial clustering may result from shared genes or shared environments. A recent population-based study from Utah interestingly showed that familial clustering can occur in both first- and second-degree relatives but also in spouses. In this large study, 1,638 CRS with nasal polyposis (CRSwNP) and 24,200 CRS sans NP (CRSsNP) patients were matched to random controls in the Utah database. The investigators found that first- and second-degree relatives had a 4.1-fold and 3.3-fold elevated risk for CRSwNP, respectively. For CRSsNP, first- and second-degree relatives also had a higher risk at 2.4-fold and 1.4-fold the baseline threshold, respectively.⁴ However, most fascinating was the two-fold increased risk of CRSsNP in spouses of CRSsNP patients.⁴

The Increasing Prevalence of Chronic Sinusitis

The prevalence of CRS has risen significantly over recent decades, with studies showing rates increasing from around 4-5% to nearly 20%.⁷ This upward trend parallels increases in other airway diseases such as asthma, suggesting shared underlying mechanisms possibly linked to environmental exposures and downstream epithelial and immune system changes. Still, unlike asthma and allergic rhinitis, CRS is grossly understudied.^8,9

Environmental Factors and Pathogenesis

Recent evidence suggests fine particulate matter (PM 2.5) may be a key environmental contributor to chronic sinusitis.¹⁰ Unlike larger particles (PM 10), PM 2.5 is more bioactive and capable of penetrating deeper into the respiratory tract, causing oxidative stress and damaging the nasal epithelial barrier. This damage triggers the release of alarmins and initiates inflammatory cascades, potentially leading to a sustained hyperinflammatory state in susceptible hosts.

Environmental exposures vary by locale, with examples including mold and damp conditions in some regions and high chemical pollutant levels in urban centers.⁷ Patients’ anecdotal experiences, such as symptom onset following mold exposure, underscore the importance of considering diverse environmental triggers in clinical assessment.

Genetics and Epigenetics

Epigenetics is the study of environmental influences on gene expression. Epigenetic studies are particularly helpful in disease states such as CRS, where multiple host or environmental factors may influence disease pathogenesis.¹¹ Although genomics is the study of an organism's complete set of DNA, including genes, non-coding regions and variations, epigenomics studies modifications to the DNA molecule that don't change the underlying base-pair sequence but can influence gene expression.^12,13 Modulation in the host’s DNA through methylation, histone modifications, non-coding RNAs, and alternative polyadenylation leads to changes in DNA expression.^12,13 Notably, epigenetic changes can persist in an individual's genes for their lifetime, and can be passed on to progeny for two to three generations, affecting the transcriptome and the proteome.¹⁴ The use of epigenetic studies is particularly helpful in disease states where a multitude of factors related to the host, family history or the environment may have incremental or interactive influences in disease pathogenesis and control.¹¹ Through epigenetics, the impact of human behaviors, diet, and environment on gene transcription has become important in cancers as well as chronic disease states, such as diabetes and asthma.^6,15–18

Epigenetic Mechanisms in Chronic Rhinosinusitis

Beyond the acute onset of insult and inflammation, CRS involves epigenetic changes—heritable modifications to DNA expression without altering the genetic code itself, which lead to a cascade of pro-inflammatory changes at the DNA, RNA, and cytokine levels.^19–21 Commonly accepted external stressors (the “environment”) include microbial pathogens, microbiome dysbiosis, and exposure to allergens and air pollution.¹

Animal models demonstrate that chronic PM 2.5 exposure leads to epigenetic downregulation of genes involved in oxidative stress response, which may explain why some patients fail to revert to a healthy baseline and develop refractory disease.²² These changes, such as DNA methylation and microRNA regulation, affect gene transcription and can lock basal cells in a persistent inflammatory state. Furthermore, a shift in the dominant type of CRS from non-type 2 to type 2 inflammatory pattern is being noted in regions and countries undergoing industrialization, and may be explained by epigenetic mechanisms.^23–25 As large-scale immigration in these regions is not occurring, detrimental environmental influences may be resulting in an increased prevalence of CRS, as well as changes in patterns of inflammation that historically underpinned CRS.

Heritability and Familial Risk: Shared Genes and Shared Environments

While traditionally considered non-heritable, emerging evidence suggests that epigenetic modifications may contribute to familial clustering of CRS across generations.^4,5,20 This evolving understanding informs patient counseling regarding familial risk while acknowledging the multifactorial nature of the disease, including the role of shared environments at home and in the workplace.

Clinical Implications and Preventative Strategies

Given the above findings, incorporating environmental histories into patient evaluations may enable us to identify factors such as occupational exposures and home environments that can exacerbate or trigger chronic sinusitis. Given the increasing evidence on the role of particulate matter in CRS, there may be a case for the use of sinonasal rinses post-exposure and considering avoidance strategies, especially for patients in high-risk occupational settings such as factories or mines.

Future Research Directions

Future investigations are needed to further define and validate the roles our genes and our environments play in the pathogenesis of CRS. We need to refine exposure assessment, potentially using personal wearable devices that capture individual-level pollutant exposures with high granularity. These should include both indoor and occupational sources. These technologies, combined with metabolomic analyses, will enhance understanding of the environment (the “exposome”) and its role in CRS pathogenesis. Large-scale genetic and epigenetic studies should be planned to further understand gene-environment interactions at the tissue level and the biological processes involved to develop novel therapeutic targets. There may also be the potential for application of novel therapeutics targeting epigenetic modifications, which are being trialed for treating cancers, including DNA transferase inhibitors and histone deacetylase inhibitors. These drugs could potentially modify the ongoing inflammatory cascade activation that characterizes medically refractory CRS and could be a useful adjunct to biologic therapies. Utilizing antioxidant therapeutics may also be an emerging treatment modality for certain patients, although further research is needed to identify suitable compounds and delivery mechanisms.

Summary of Practical Takeaways

• CRS prevalence is rising, paralleling other airway diseases.
• PM 2.5 exposure is a significant environmental factor causing epithelial damage and inflammation.
• Epigenetic changes contribute to disease chronicity and represent a promising therapeutic target.
• Environmental and occupational histories are important factors in patient management.
• Preventative measures such as sinus rinses and exposure avoidance should be emphasized.
• Familial risk may be influenced by epigenetics and shared environments.
• Advances in exposure tracking and genetic research will drive future understanding and treatment.

References

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