Host Genetic Factors Influencing COVID-19 Susceptibility and Severity: A Narrative Review

Abstract

Background: COVID-19 presents highly variable clinical outcomes, and growing evidence shows that host genetic factors significantly influence susceptibility to infection and disease severity. Understanding these contributions is essential for improving risk stratification and guiding targeted therapeutic approaches. Objective: To review current evidence on genetic determinants of COVID-19 susceptibility and severity, highlighting key pathways, population-specific findings, and implications for precision medicine. Methods: A narrative review was conducted using PubMed and major COVID-19 genetics consortia outputs (up to 2025), integrating genome-wide association studies, meta-analyses, exome and whole-genome sequencing data, and population-based studies investigating the impact of common and rare variants related to interferon signaling, antiviral responses, inflammatory pathways, and viral entry. Findings were synthesized with available evidence from clinical trials targeting genetically implicated pathways. Results: Genetic studies consistently identify variants affecting interferon pathways, antiviral effector mechanisms, and inflammatory regulators as major contributors to severe COVID-19. Common variants in genes such as IFNAR2, TYK2, OAS1–3, DPP9, CCR2, ACE2, and TMPRSS2 influence susceptibility or clinical progression. Rare, high-impact variants, especially in TLR7, significantly increase the risk of critical illness. Population-specific analyses reveal additional modifiers of severity. Therapeutic responses to interferon-based agents and JAK inhibitors align with the biological pathways highlighted by genetic findings. Interpretation is limited by heterogeneous severity phenotypes, ancestry imbalances in available datasets, modest effect sizes for common variants, and temporal shifts in variants, vaccination, and clinical care. Conclusion: Host genetics substantially modulates COVID-19 outcomes, acting through both common and rare variants in innate immunity, antiviral defense, and inflammatory pathways. However, cross-study comparability and generalizability are constrained by variable case definitions, unequal ancestry representation, limited genotype-stratified clinical evidence, and evolving viral and population immunity contexts. Integrating genomic insights into clinical practice may improve early risk identification and support more personalized therapeutic strategies for current and future infectious threats. However, most genetic associations have modest effect sizes and are ancestry-dependent, and translation into routine clinical practice remains limited.