A recent study (1) published in the Journal of the American Medical Association (JAMA), entitled, “Racism, Not Race, Drives Inequality Across the COVID-19 Continuum,” the authors make the case that societal factors have caused many of the COVID-19 deaths in underprivileged communities. They compare and contrast two studies (2, 3), one in Bronx, NY, and the other in Milwaukee, WI, which concluded that that disparities in housing, education, economic opportunity, and savings account for most if not all of the differences in the 2.5 to 4.5 times higher death rates among African American, Hispanic, and Native American populations compared to white populations. The authors make a case for the need to conduct focused studies on the effects of poverty and lack of opportunity on disease outcomes.

Scientists have yet to understand the divergence in the pathology of disease among the poor compared with the more privileged. At its core is a simple question: “How does poverty, food insecurity, exposure to physically unsafe environments, etc., bring about the immunological changes that are key to the disease pathway seen in COVID-19?” An answer to this question not only would help us do a better job of predicting and managing infectious diseases in the most vulnerable but can also inform potential new therapies that can benefit everyone.

COVID-19 has claimed more than 600,000 lives in the U.S. so far. A better biological understanding is needed of how and why the outcomes of SARS-CoV-2 infections vary so greatly between sub-populations, even those living in close proximity to each another, for example East Palo Alto vs. Palo Alto or Hunters Point vs. Twin Peaks in San Francisco.

The answer, to some degree, may rest in epigenetics, an emerging area of research focused on the regulation of genes via structural changes in chromosomes which change the accessibility of regulatory transcription factors to those genes. DNA and protein modifications, such as DNA methylation, lead to these structural changes after environmental stressors are experienced, and those changes are now known to be passed down through multiple generations. Conditions as wide-ranging as post-traumatic stress disorder (PTSD), severe anxiety, cancer, and autoimmune diseases have been directly linked to epigenetic changes. Epigenetic modifications may be cell-type-specific. Though it is clear that multiple types of stressors lead to epigenetic changes in both germ line and somatic cells (4-6), the pathways affected by those stressors are still being elucidated. Pathways that, when overstimulated in some people, lead to PTSD, major depressive disorders, and other systemic effects including dysfunctional immune response.

Evidence is also mounting on the role that epigenetics may play on how opportunistic pathogens can evade the immune system. This is especially important during the initial, critical stage of infection when early expression of molecules such as interferon can lead to a mild form of viral disease vs. a life-threatening inflammatory response when viral infection is detected late. Given the differences in severe vs. mild/sub-clinical infections, as well as the vast disparities in who becomes infected and who dies, a better understanding of the socio-economic factors that affect these differences is vital not only for this pandemic, but also for future threats to public health and the nation’s health security.

As we have observed with the multiple failures of genome-wide association studies (7) and the emerging fields of epigenetics, it is clear that what is needed is an unbiased, epigenetically based survey of survivors and the deceased, as well as those who suffer from long-haul COVID-19 vs. those who developed an acute but quickly resolved infection. Additionally, given the vast differences in the microbiota resultant from diet, exercise, and environment, as well as stressors (especially those that do not show up as PTSD, anxiety, or depression) which have an effect on gene expression, studies seeking this understanding must take such factors as gut microbiome composition into account when designing their methodologies. As multiple studies have linked gut microbiota to changes in neural (8) and immune gene expression patterns (9), epigenetic studies will help us understand the proclivity of changes in gene expression caused by microbial populations and vice-versa, as they are doing now for obesity (10). Such studies will do much to inform our understanding of healthy immune and neurological responses as they relate to the gut microbiome.

The answer, to some degree, may rest in epigenetics, an emerging area of research focused on the regulation of genes via structural changes in chromosomes which change the accessibility of regulatory transcription factors to those genes. DNA and protein modifications, such as DNA methylation, lead to these structural changes after environmental stressors are experienced, and those changes are now known to be passed down through multiple generations. Conditions as wide-ranging as post-traumatic stress disorder (PTSD), severe anxiety, cancer, and autoimmune diseases have been directly linked to epigenetic changes. Epigenetic modifications may be cell-type-specific. Though it is clear that multiple types of stressors lead to epigenetic changes in both germ line and somatic cells (4-6), the pathways affected by those stressors are still being elucidated. Pathways that, when overstimulated in some people, lead to PTSD, major depressive disorders, and other systemic effects including dysfunctional immune response.

[1] Khazanchi R, Evans CT, Marcelin JR. Racism, Not Race Drives Inequity Across the COVID-19 Continuum. JAMA Network Open. 2020;3(9):e2019933. doi:10.1001/jamanetworkopen.2020.19933

[2] Kabarriti R, Brodin NP, Maron MI, et al. Association of race and ethnicity with comorbidities and survival among patients with COVID-19 at an urban medical center in New York. JAMA Netw Open. 2020;3(9):e2019795. doi:10. 1001/jamanetworkopen.2020.19795

[3] Muñoz-Price LS, Nattinger AB, Rivera F, et al. Racial disparities in incidence and outcomes among patients with COVID-19. JAMA Netw Open. 2020;3(9):e2021892. doi:10.1001/jamanetworkopen.2020.21892

[4] Pfeiffer, J.R., Mutesa, L. & Uddin, M. Traumatic Stress Epigenetics. Curr Behav Neurosci Rep 5, 81–93 (2018). https://doi.org/10.1007/s40473-018-0143-z

[5] Jiang, S., Postovit, L., Cattaneo, A., Binder, E.B., Aitchison, K.J. Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma. Frontiers in Psychiatry 10, 808 (2019) https://www.frontiersin.org/article/10.3389/fpsyt.2019.00808 and https://doi.org/10.3389/fpsyt.2019.00808

[6] Jawaid A, Roszkowski M, Mansuy IM. Chapter Twelve - Transgenerational Epigenetics of Traumatic Stress, Editor(s): Bart P.F. Rutten in: Progress in Molecular Biology and Translational Science. Academic Press 158, 273-298 (2018). https://doi.org/10.1016/bs.pmbts.2018.03.003

[7] https://www.wired.com/2008/09/why-do-genome-wide-scans-fail/

[8] Ma, Q., Xing, C., Long, W. et al. Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis. J Neuroinflammation 16, 53 (2019). https://doi.org/10.1186/s12974-019-1434-3

[9] Zheng, D, Liwinski, T., Enilav, E. Interactions between microbiota and immunity in health and disease. Cell Research 30, 492-506 (2020) https://www.nature.com/articles/s41422-020-0332-7

[10] Sharma M, Li Y, Stoll ML, Tollefsbol TO. The Epigenetic Connection Between the Gut Microbiome in Obesity and Diabetes. Front Genet. 2020;10:1329. Published 2020 Jan 15. doi:10.3389/fgene.2019.01329