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Host genetic variations in particular those related to the immune responses determine the patients' susceptibility and COVID\u201019 severity and pathophysiology. Gene polymorphisms such as single nucleotide polymorphisms (SNPs) of interferons,<jats:italic>TNF<\/jats:italic>,<jats:italic>IL1, IL4, IL6, IL7, IL10<\/jats:italic>, and<jats:italic>IL17<\/jats:italic>predispose patients to the severe form of COVID\u201019 or severe acute respiratory syndrome coronavirus\u20102 (SARS\u2010COV\u20102). These variations mainly alter the gene expression and cause a severe response by B cells, T cells, monocytes, neutrophils, and natural killer cells participating in a cytokine storm. Moreover, cytokines and chemokines SNPs are associated with the severity of COVID\u201019 and clinical outcomes depending on the corresponding effect. Additionally, genetic variations in genes encoding toll\u2010like receptors (TLRs) mainly<jats:italic>TLR3<\/jats:italic>,<jats:italic>TLR7<\/jats:italic>, and<jats:italic>TLR9<\/jats:italic>have been related to the COVID\u201019 severe respiratory symptoms. The specific relation of these mutations with the novel variants of concern (VOCs) infection remains to be elucidated. Genetic variations mainly within genes encoding proinflammatory cytokines, cytokine receptors, and TLRs predispose patients to COVID\u201019 disease severity. 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