Abstract
OBJECTIVE: Interindividual variability in the clinical progression of COVID-19 may be explained by host genetics. Emerging literature supports a potential inherited predisposition to severe forms of COVID-19. Demographic and inflammatory characteristics of COVID-19 suggest that acquired hematologic mutations leading to clonal hematopoiesis (CH) may further increase vulnerability to adverse sequelae. This review summarizes the available literature examining genetic predispositions to severe COVID-19 and describes how these findings could eventually be used to improve its clinical management. DATA SOURCES: A PubMed literature search was performed. STUDY SELECTION: Studies examining the significance of inherited genetic variation or acquired CH mutations in severe COVID-19 were selected for inclusion. DATA EXTRACTION: Relevant genetic association data and aspects of study design were qualitatively assessed and narratively synthesized. DATA SYNTHESIS: Genetic variants affecting inflammatory responses may increase susceptibility to severe COVID-19. Genome-wide association studies and candidate gene approaches have identified a list of inherited mutations, which likely alter cytokine and interferon secretion, and lung-specific mechanisms of immunity in COVID-19. The potential role of CH in COVID-19 is more uncertain at present; however, the available evidence suggests that the various types of acquired mutations and their differential influence on immune cell function must be carefully considered. CONCLUSIONS: The current literature supports the hypothesis that host genetic factors affect vulnerability to severe COVID-19. Further research is required to confirm the full scope of relevant variants and the causal mechanisms underlying these associations. Clinical approaches, which consider the genetic basis of interindividual variability in COVID-19 and potentially other causes of critical illness, could optimize hospital resource allocation, predict responsiveness to treatment, identify more efficacious drug targets, and ultimately improve outcomes.