Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

Abstract

BACKGROUND Epidemiological studies indicate that as many as 20% of individuals who test positive for COVID-19 develop severe symptoms that can require hospitalization. These symptoms include low platelet count, severe hypoxia, increased inflammatory cytokines and reduced glomerular filtration rate. Additionally, severe COVID-19 is associated with several chronic co-morbidities, including cardiovascular disease, hypertension and type 2 diabetes mellitus. The identification of genetic risk factors that impact differential host responses to SARS-CoV-2, resulting in the development of severe COVID-19, is important in gaining greater understanding into the biological mechanisms underpinning life-threatening responses to the virus. These insights could be used in the identification of high-risk individuals and for the development of treatment strategies for these patients. METHODS As of June 6, 2020, there were 976 patients who tested positive for COVID-19 and were hospitalized, indicating they had a severe response to SARS-CoV-2. There were however too few patients with a mild form of COVID-19 to use this cohort as our control population. Instead we used similar control criteria to our previous study looking at shared genetic risk factors between severe COVID-19 and sepsis, selecting controls who had not developed sepsis despite having maximum co-morbidity risk and exposure to sepsis-causing pathogens. RESULTS Using a combinatorial (high-order epistasis) analysis approach, we identified 68 protein-coding genes that were highly associated with severe COVID-19. At the time of analysis, nine of these genes have been linked to differential response to SARS-CoV-2. We also found many novel targets that are involved in key biological pathways associated with the development of severe COVID-19, including production of pro-inflammatory cytokines, endothelial cell dysfunction, lipid droplets, neurodegeneration and viral susceptibility factors. CONCLUSION The variants we found in genes relating to immune response pathways and cytokine production cascades, were in equal proportions across all severe COVID-19 patients, regardless of their co-morbidities. This suggests that such variants are not associated with any specific co-morbidity, but are common amongst patients who develop severe COVID-19. Among the 68 severe COVID-19 risk-associated genes, we found several druggable protein targets and pathways. Nine are targeted by drugs that have reached at least Phase I clinical trials, and a further eight have active chemical starting points for novel drug development. Several of these targets were particularly enriched in specific co-morbidities, providing insights into shared pathological mechanisms underlying both the development of severe COVID-19, ARDS and these predisposing co-morbidities. We can use these insights to identify patients who are at greatest risk of contracting severe COVID-19 and develop targeted therapeutic strategies for them, with the aim of improving disease burden and survival rates.

Why COVID-19 is less frequent and severe in children: a narrative review

“…In addition to possible involvement of several other genes (e.g., ABO blood type and Mediterranean fever gene) [ 99 ], genetic variations in these gateways might be influenced by the societies geographically. Using a combinational analysis approach, Taylor and colleagues identified 68 protein-coding genes that were highly associated with severe COVID-19 [ 100 ]. Ouyang et al revealed that the number of differentially expressed genes ( DEGs ) increased by disease progression and decreased after initial treatment.…”

Host genetic factors and susceptibility to SARS‐CoV‐2 infection

“…Along these same lines, Taylor et al (2020) identified 68 genes involved with response to SARS‐CoV‐2 infection. These included loci that encode pro‐inflammatory cytokines, endothelial cell dysfunction, and viral susceptibility factors, among other cellular products.…”

“…Some people infected with SARS‐CoV‐2 become extremely sick, while others express only mild symptoms or are asymptomatic. Among the severe symptoms are increased inflammatory cytokines, low platelet count, severe hypoxia, and reduced kidney function, (Taylor et al, 2020). Preexisting conditions or chronic co‐morbidities such as diabetes, hypertension, cardiovascular disease, cancer and chronic respiratory illnesses such as asthma and COPD also put people at higher risk for infection and severe disease symptoms (Caramelo, Ferreira, & Oliveiros, 2020; Guan et al, 2020; Jain & Yuan, 2020; Taylor et al, 2020; Wang et al, 2020; Yang et al, 2020).…”

“…Among the severe symptoms are increased inflammatory cytokines, low platelet count, severe hypoxia, and reduced kidney function, (Taylor et al, 2020). Preexisting conditions or chronic co‐morbidities such as diabetes, hypertension, cardiovascular disease, cancer and chronic respiratory illnesses such as asthma and COPD also put people at higher risk for infection and severe disease symptoms (Caramelo, Ferreira, & Oliveiros, 2020; Guan et al, 2020; Jain & Yuan, 2020; Taylor et al, 2020; Wang et al, 2020; Yang et al, 2020). In addition, older adults have a much greater risk for infection and severe symptoms than younger individuals, although not exclusively so, and men are at higher risk for infection and mortality than are women (Chakravarty et al, 2020; Li et al, 2020; Zhou, Chen, et al, 2020; Zhou, Yu, et al, 2020).…”

“…Nevertheless, the goal of ongoing COVID‐19 research is to identify genetic variation that will improve the clinical management of this disease and foster better patient outcomes (Murray et al, 2020; The COVID‐19 Host Genetics Initiative, 2020). For example, of the 68 severe COVID‐19 risk‐associated genes identified by Taylor et al (2020), several of them yield protein products that can be targeted for drug development, with drugs for nine of these targets having reached Phase I clinical trials. Others have suggested that “[p]airing HLA typing with COVID‐19 testing where feasible could improve assessment of viral severity in the population” (Nguyen et al, 2020: e00510), thereby allowing prioritization of individuals with high‐risk HLA types for vaccination.…”