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Association of genetic polymorphisms with COVID-19 infection and outcomes: An updated meta-analysis based on 62 studies

Dec 2023  
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Meta-analysis of 62 studies with 19,600 COVID-19 cases showing certain genetic polymorphisms associated with COVID-19 infection risk, severity, and mortality. Specifically, the ACE I/D polymorphism was associated with lower COVID-19 infection risk, while IFITM3 rs12252 and TMPRSS2 rs12329760 polymorphisms were associated with higher infection risk. For COVID-19 severity, polymorphisms in ACE2, IFITM3, TMPRSS2, and VDR genes were associated with increased or decreased severity risk. Finally, the IFITM3 rs12252 variant C allele was associated with significantly higher COVID-19 mortality risk. The findings indicate these genetic factors may help predict COVID-19 susceptibility and outcomes, and could potentially inform personalized treatment approaches, though further research is still needed.
Patients with VDR genetic variants may potentially benefit more from vitamin D treatment, and patients with TMPRSS2 variants may potentially benefit more from TMPRSS2 inhibitors.
Bromhexine efficacy may vary depending on the degree of TMPRSS-dependent fusion for different variants Peacock, Willett.
Currently there are 7 bromhexine studies and meta analysis shows:
Mortality77% lower [-39‑96%]
Ventilation89% lower [16‑99%]
ICU admission82% lower [23‑96%]
Hospitalization10% lower [-8‑24%]
Cases62% fewer [-11‑87%]
Ren et al., 14 Dec 2023, Iran, peer-reviewed, 6 authors. Contact:,
This PaperBromhexineAll
Association of genetic polymorphisms with COVID-19 infection and outcomes: An updated meta-analysis based on 62 studies
Hongyue Ren, Yanyan Lin, Lifeng Huang, Wenxin Xu, Deqing Luo, Chunbin Zhang
Heliyon, doi:10.1016/j.heliyon.2023.e23662
Background: The relationship between genetic polymorphisms and coronavirus disease 2019 remains to be inconsistent. This meta-analysis aimed to provide an updated evaluation of the role of genetic polymorphisms in the infection, severity and mortality of COVID-19 based on all available published studies. Methods: A systematic search was performed using six databases: PubMed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Wanfang. Summary odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were used to calculate the genotypic comparison. All statistical analyses were conducted in Stata 12.0. Results: A total of 62 studies with 19600 cases and 28899 controls was included in this metaanalysis. For COVID-19 infection, ACE Ins/Del polymorphism might be related with significantly decreased risk of COVID-19 infection under dominant, homozygote and allelic models. Meanwhile, the IFITM3 rs12252 and TMPRSS2 rs12329760 polymorphisms were significantly associated with the increased risk of COVID-19 infection under one or more models. Regarding COVID-19 severity, ACE2 rs2074192, ACE2 rs2106809, IFITM3 rs12252 and VDR rs1544410 polymorphisms might be related with significantly increased risk of COVID-19 severity in one or more models. Moreover, the analysis of TMPRSS2 rs2070788 indicated that a variant A allele decreased the risk of COVID-19 severity in recessive model. For COVID-19 mortality, the variant C allele of IFITM3 rs12252 polymorphism might be related with significantly increased risk of COVID-19 mortality under all genetic models. Conclusions: This meta-analysis indicated that he infection, severity or mortality of COVID-19 were related to the above genetic polymorphisms, which might provide an important theoretical basis for understanding the clinical feature of COVID-19 disease.
Declaration of competing interest The author (s) declare that they have no competing interests. Appendix A. Supplementary data Supplementary data to this article can be found online at
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