**9. Genetic polymorphism and therapy effectiveness**

COVID-19 may be inactivated or partially treated by the following approaches: ACE2 receptor attaching site blocking either by antibody or specific ligand or using ACE2 soluble form that can neutralize the virus by binding the virus spike protein, and, yet, cover ACE2 binding site on the host cell surface and reducing the tissue injury. The genetic polymorphisms of cytochrome (CYP) 2D6 can affect drug metabolism using this approach, which contains 50% currently using drugs [114]. The metabolism of these genes can be increased by these polymorphisms and in turn, reduce their efficiency or significantly decline their metabolism causing drug toxicity [115]. Slow drug metabolizers permit toxic effects of the medications as chloroquine to become accumulated and resulting in cardiac problems with an increased hazard of cardiac arrest, specifically in diabetes and obesity patients. CYP2D6 Polymorphism is much high in Asians and African Americans [116–118], which extremely influenced by this disorder. One Korea study studying Lupus disease demonstrated considerable variation in the level of hydroxychloroquine due to polymorphisms of CYP2D6 [119]. This may explain the clinical outcomes differences when using this drug. Because of the metabolism abnormalities due to these genetic polymorphisms, resistant malaria strains will be arising [120–122]. Heart failure patients can be affected by the same CYP 2D6 gene polymorphisms since it is accountable for metoprolol metabolism [123, 124]. These gene variants affect several other medications such as barbiturates, Isoniazid (INH), serotonin reuptake inhibitor (omeprazole hydralazine sulfasalazine, etc.) [125]. Individuals with CYP2D6 polymorphisms and the HO-1 GT allele make therapy and disease outcomes challenging. Some of the patients who carry these polymorphisms will respond perfectly to drugs and have a low risk of COVID-19 patients to develop complications such as multiorgan failure and ARDS, while other patients will express drug toxicity levels and multiorgan problems [115]. This can describe why clinicians are unable to predict the multiorgan failure with COVID −19 disease and different outcomes from using 4-aminoquinolones.

*Genetic Variation*

(G > A) were correlated with aggressive H7N9, H1N1, and increased lung expression of TMPRSS2 [92]. A study by Hou et al., indicated that 4% of nonidentical variants of TMPRSS2 are stop-codon mutations, Meanwhile, 59% are harmful mutations in TMPRSS2 coding regions [93]. The harmful variants (p.Arg240Cys, p.Val160Met, p.Gly181Arg, p.Pro335Leu, p.Gly432Ala, and p.Gly259Ser) in the coding region of TMPRSS2, are the same with somatic alterations arising in various types of cancer. In the same contest, Hou et al. found that, the p. Asp435Tyr which is a key site for catalytic residue binding of TMPRSS2 has unique low-frequency allele, but predominant SNPs in TMPRSS2 and offer possible descriptions for differential genetic infectivity to COVID-19 and for risk influences, such as those with tumor and male patients. By using the analysis of single-cell RNA-seq, Schuler et al. revealed that the expression of TMPRSS2 was upregulated in ciliated cells and alveolar epithelial type 1 cells and increased with humans aging [94]. This observation indicates that the developmental TMPRSS2 expression regulation may have a role in the relative protection of the children and infants from COVID-19 infection. Yet, it might be of great importance to investigate the link between TMPRSS2 polymorphisms and the

age relationship with COVID-19 susceptibility (**Figure 3**).

**COVID-19 severity**

acute inflammation conditions.

**8. BCL11A polymorphisms**

**7. Heme oxygenase-1 enzyme (HO-1) genetic polymorphisms and** 

cations perhaps have longer GT sequences and decreased vessel hemostasis. COVID-19 disease has poor effects in diabetic and obese individuals, maybe because those people are already having high interleukin 6 levels of (IL-6) and they are in a proinflammatory state due to leptin and insulin resistance [102, 103]. As a result, the negative clinical outcomes of COVID-19 infection in obese patients was recorded [103]. Peterson et al. have revealed that obesity raises high-density lipoprotein (HDL) oxidation [104]. Oxidized HDL (Ox-HDL) is thought to produce proinflammatory cytokines by the direct action on adipocyte stem cells [105]. Ox-HDL initiates an inflammatory cascading with inflammatory cytokines, tumor necrosis factor (TNF), interleukins (IL-6, IL-1), and increasing of Angiotensin II (ANG II), a biomarker for early cardiovascular system disorders [104]. This made the obese individuals are more sensitive to heart failure due to infection of COVID-19 [106]. Up-regulation of HO-1-derived bilirubin may enhance the COVID-19 bad effect, this risk was reduced by an increased HO-1 level [107, 108]. Hence, up-regulation of the level of HO-1 with pharmacological treatment [109] may have valuable action in

BCL11A Genetic polymorphisms were correlating to produce fetal hemoglobin

in overall population, and these genetic variants were later found to be able to

Many studies demonstrated that the HO-1 gene polymorphisms, particularly the promoter region GT dinucleotide repeat mutation regulates the inducibility of HO-1 to ROS [95–101]. Subjects with more GT repeats have been believed to be more sensitive to cardiovascular endothelium diseases such as atherosclerosis coronary artery disease and aortic aneurysm s [95, 98, 99]. The lower Expression level of HO-1 in those with more GT repeats make the patients to be more affected to decrease endothelial hemostasis and inflammation [95–101]. While, GT sequences short alleles are correlated with increased HO-1 inducibility, which in turn reduced inflammation and enhanced cytoprotection [101]. Patients with COVID-19 compli-

**184**
