**10. Personalized medicine guided by host genetic of COVID-19**

SARS-CoV-2 inhibition can be done by spike protein and ACE2 differential glycosylation [126]. Several polymorphisms, such as p.Pro389His, p.Met383Thr and p.Asp427Tyr slightly inhibited by hydroxychloroquine. This can be clarifying why hydroxychloroquine treatment was not significantly in a different hospital than others [127]. However, more pharmacogenomics experiments between the genetic data and drug response from COVID-19 patients are extremely needed. The viral entry to the host cell by binding to the cell membrane through S protein can be blocked by TMPRSS2 [88]. The SARS-CoV-2 pathogenesis and infection depend on the TMPRSS2 presence, in a high pH environment [128, 129]. The inhibitor of endosomal acidification such as hydroxychloroquine and CatB/L inhibitors might work only in absence of TMPRSS2- in SARS-CoV-2 infected and may not work or has no or less effective in patients with TMPRSS2 wild-type [128]. So far, the populations with missense polymorphisms and stop-gained of TMPRSS2 polymorphisms may be good sensitive to treatment with hydroxychloroquine. Furthermore, the patients who carry TMPRSS2 and ACE2 wildtype, a mix of hydroxychloroquine or chloroquine with camostat may have the best clinical advantage. The ACE2 can be cleaved by TMPRSS2 at Arginine 697 to 716 [130], which improves viral entry. Thus, patients with, p.Arg710Cys p.Arg708Trp, p.Arg716Cys and p.Arg710His polymorphisms in ACE2 might have fewer symptoms of COVID-19 disease as the cleavage site of ACE2 gene loses by these polymorphisms (**Figure 3**) [113].
