Risk-focused Differences in Molecular Processes Implicated in SARS-CoV-2 Infection: Corollaries in DNA Methylation and Gene Expression

Abstract Background Understanding the molecular basis of susceptibility factors to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health imperative. It is well-established that males are more likely to acquire SARS-CoV-2 infection and exhibit more severe outcomes. Similarly, exposure to air pollutants and pre-existing respiratory chronic conditions like asthma and chronic obstructive respiratory disease (COPD) confer an increased risk to coronavirus disease 2019 (COVID-19). Methods We investigated molecular patterns associated with risk factors in 398 candidate genes relevant to COVID-19 biology. To accomplish this, we downloaded DNA methylation and gene expression datasets from publicly available repositories (GEO and GTEx portal) and utilized data from our unpublished controlled human exposure study. Results First, we observed sex-biased DNA methylation patterns in autosomal immune genes such as NLRP2, TLE1, GPX1, and ARRB2 (FDR <0.05, magnitude of DNA methylation difference Δβ >0.05). Second, our analysis on the X-linked genes identified sex associated DNA methylation profiles in genes such as ACE2, CA5B, and HS6ST2 (FDR <0.05, Δβ >0.05). These associations were observed across multiple respiratory tissues (lung, nasal epithelia, airway epithelia, and bronchoalveolar lavage) and in whole blood. Some of these genes, like NLRP2 and CA5B, also exhibited sex-biased expression patterns. Third, we identified modest DNA methylation changes in CpGs associated with PRIM2 and TATDN1 (FDR <0.1, Δβ >0.05) in response to particle-depleted diesel exhaust in bronchoalveolar lavage. Finally, we captured a DNA methylation signature associated with COPD diagnosis in a gene involved in nicotine dependence (COMT) (FDR <0.1, Δβ >0.05). Conclusion Our findings on sex differences are of clinical relevance given they potentially point to an exaggerated immune response in males. We also found tissue-specific DNA methylation differences in response to particulate exposure potentially capturing an NO2 effect – a contributor to COVID-19 susceptibility. While we identified a molecular signature associated with COPD, all COPD-affected individuals were smokers, which may either reflect an association with the disease, smoking, or may highlight a compounded effect of these two risk factors in COVID-19. Overall, the findings point towards the molecular basis of variation in susceptibility factors that may partly explain disparities in SARS-CoV-2 infection.

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