Table 1.
Main COVID‐19 associated genes and their polymorphisms
| Gene | Chromosome | Function in COVID‐19 | Polymorphism (SNP) | Study population | Result | References |
|---|---|---|---|---|---|---|
| ACE1 | 17 | ACE‐1 and ACE‐2 are angiotensin peptide cleavers, with ACE‐1 cleaving Ang I and creating Ang II. At the same time, ACE‐2 cleaves Ang II and produces Ang III, which triggers vascular constriction and bronchoconstriction, enhances endothelial dysfunction, fibrosis, and inflammation, and continues the progression of ARDS and lung collapse cases with COVID‐19. | rs1799752 | Korea, Europe | Evidence shows that the ACE1 I/D polymorphism might be implicated in various clinical diseases induced by SARS‐CoV‐2 diseases such as renal damage, pneumonia, ischemic stroke, and immunological reaction, including the cytokine storm. | 93 , 94 |
| ACE 2 | Xp22.2 | It has been discovered that the SARS‐CoV‐2 S protein recognizes the ACE2 ligand. This recognition promotes the virus' binding to the cell. | rs2106806, rs6629110 | Spain | According to the current investigation findings, the minor A allele inside rs2106806 enhances the risk of developing severe COVID‐19. | 95 , 96 |
| ACE 2 | – | – | rs2285666 | India | In this study, researchers discovered for the first time a positive and statistically significant connection between alternative allele (T or A) of rs2285666 with a reduced infection and mortality rate in Indian communities. | 97 |
| ACE 2 | – | – | S19P, I21T/V, E23K, A25T, K26R, T27A, E35D/K, E37K, Y50F, N51D/S, M62V, N64K, K68E, F72V, E75G, M82I, T92I, Q102P, G220S, H239Q, G326E, E329G, G352V, D355N, H378R, Q388L, P389H, E467K, H505R, R514G/*, and Y515C | Europeans, Africans, Asians, and Americans | For the virus to enter and infect the host, these variations played a central role. According to recent research, the uncommon variations of human ACE2 appear to become one of the determining variables linked with adaptation in the fight toward SARS‐CoV‐2. | 98 |
| ACE 2 | – | – | rs61299115, rs11088551, and rs4303794 | Asian and African descents in Israel | The combination of the three SNPs, which are very frequent in the overall population (25%–36%) but are relatively uncommon in the East Asian and Korean populations, suggests that TMPRSS2 is expressed at a lesser rate in these groups. This, together with the differences identified in the promoter of ACE2, might lead to the conclusion that COVID‐19 has varied pathogenesis and outcome in different societies. | 7 |
| TMPRSS2 | 21q22.3 | An additional requirement for viral entrance to the target cell is S priming by cell‐surface proteases, including the TMPRSS2, which also is accomplished by degradation of the virus's S protein at the S1/S2 and S2 domains. | p.Val160Met | Indonesia | However, while the current analysis found no connection between the p.Val160Met variant and illness severity, they did notice a possible connection between the TMPRSS2 (pVal160Met) variation and viral load in subjects with COVID‐19. | 10 |
| TMPRSS2 | – | – | rs383510 | German | This study demonstrated that the intron variation rs383510 in the gene TMPRSS2 is related to an elevated risk of SARS‐CoV‐2 disease in a German population. | 99 |
| IFITM3 | – | – | rs6598045 | Worldwide | A noteworthy finding of this investigation was discovering a significant connection between the death rate of COVID‐19 and the allele frequency of the rs6598045 SNP of the IFITM3 locus. | 100 |
| TMPRSS2 | – | – | rs3787946, rs9983330, rs12329760, rs2298661, and rs9985159 | Italy | Furthermore, while comparing the critically ill patients to the reference persons, it was discovered that the alleles with minor frequency were less frequently identified, indicating that they may have a protective function against the advancement of the disease. Unexpectedly, four of the five SNPs were found to be repeated in two Asian‐derived cohorts, but just two SNPs were found to be replicated in a case series of African descent. Furthermore, we confirmed the relationship between the rs12329760 SNP and Italian nationality in a separate case‐control cohort of Italian origins, which was previously published. These findings clearly imply that the gene 21q22.3 is a new susceptibility locus to an adverse outcome of COVID‐19 and that people of diverse ethnic backgrounds might share the molecular processes behind this genetic propensity. | 101 |
| TMPRSS2 | – | – | p.V197M (p.Val197Met) (rs12329760) | Finland, Italy | It was discovered that there is a frequent variation of the gene p.V197M (p.Val197Met) (rs12329760) which has a detrimental impact on the protease and beneficial effects on the patients. It is thought to play a significant role among two sub‐groups, namely, young men and older women and those with co‐morbidities. The variant amplitude is more prevalent in individuals who were moderately influenced by the disease and did not demand inpatient care or mechanical ventilation than those who were more significantly affected, who mandated mechanical ventilation or intubation. | 102 |
| CD26 | 2 | In recent research, it has been revealed that SARS‐CoV‐2 interacts with the DPP4/CD26 receptor as it enters cells of the respiratory system. It indicates that the link between the S protein (SARS‐CoV‐2) and the DPP4/CD26 is a critical component in the hijacking and pathogenicity of the virus. | rs13015258 | Worldwide | rs13015258, a 5′ UTR polymorphism from CD26, has been shown to have a vital function in controlling the expression of essential regulatory genes, which may be implicated in the internalization of SARS‐CoV‐2. Increased expression of CD26 caused by epigenetic alteration at the rs13015258‐C allele was discovered to be necessary, and this might underlie the increased mortality rate associated with SARS‐CoV‐2 infection among patients with type 2 diabetes. | 103 , 104 |
| IFITM3 | 11 | IFITM has a vital antiviral function in the body since it prevents viruses from crossing through the lipid bilayer of the cell. Variants of the IFITM3 gene are related to clinical responses to influenza and other viruses. | rs12252 | China | In recent years, it has been shown that homozygosity for the C allele of the rs12252 gene in the IFITM3 gene is related to a much more severe infection in an age‐dependent fashion. This supports the hypothesis that IFITM3 plays a function in the disease process and provides the potential for early specialized treatment in at‐risk people, among other things. | 88 , 105 |
| IL‐6 | 7p15.3 | Growing evidence suggests an upsurge of IL‐6 in COVID‐19 critically ill patients, and the presence of this rise is associated with the severity of the illness and the risk of death. | rs1800796/rs1800795 | Worldwide | The polymorphisms in the IL‐6 gene at the rs1800796/rs1800795 loci were studied in communities from India, Mexico, Turkey, Brazil, Russia, Italy, South Africa, the Netherlands, and Greece. The GG genotype was found in most of the communities from these countries, whereas the GC genotype was found in the majority of the societies from China, Spain, Sweden, Poland, Germany, and the United Kingdom. | 106 , 107 |
| Only the Japanese population exhibited the CC genotype for the rs1800796 variant. | ||||||
| HLA | 6 | Considering that HLA plays an essential role in the immunological reactions to pathogens and the pathogenesis of infectious diseases, it has been suggested that HLA diversity in a population might be associated with COVID‐19 occurrence. | HLA‐A*24:02 | China | According to a study conducted in Wuhan, there is a significant association between the HLA‐A*24:02 gene as well as the risk of developing COVID‐19 in the Han population. | 92 , 108 |
| ABO | 9q34.2 | An accumulating body of data shows that the ABO blood type may play a major role in the immunopathology of SARS‐CoV‐2 disease, with group O persons being less likely to test positive and group A persons being more susceptible to infection and more likely to suffer from severe illness. | 3p21.31 and 9q34 | Italy | 9q34 contains the ABO blood group loci, and blood‐group‐specific research discovered a stronger connection between being A‐positive and having a greater chance of contracting covid19 than previously thought. | 109 , 110 |
| DBP | 4q11q13 | It was shown that having higher 25‐hydroxyvitamin D levels was linked with a considerably reduced amount of total lung participation while having low 25‐hydroxyvitamin D levels was related to an increased risk of death. It brought attention to the relevance of the polymorphisms of vitamin D binding protein (DBP), the main transporter of vitamin D, and performs a potentially underappreciated role in the pathophysiology of COVID‐19 infection. | rs7041 and rs4588 | Turkey | Between both the occurrence (per million) and death rates (per million), as well as the GT genotype (P.05), significant positive associations were discovered. In contrast, a significant negative relationship was discovered between both the occurrence (per million) and death rates (per million), as well as the TT genotype atrs7041 locus amongst the communities (p < 0.05). In conclusion, the differences in the occurrence of COVID19 and the death rates associated with it may be linked with the DBP variants rs7041 and rs4588 were shown to have different effects on vitamin D metabolism. | 111 , 112 |
| GSTT1 | 1p13.3 | The GSTT1 and GSTM1 deficient variants are linked with an increased risk of various oxidative stress‐related complex illnesses. It is widely recognized that oxidative stress is a significant contributor to the development of viral respiratory diseases. Pulmonary fibrosis is one of the most serious consequences of COVID‐19 illness, which is characterized by high levels of oxidative stress in the body. | GSTM1 and GSTT1 | India | Patients with the GSTM1+/+ and GSTT1−/− genotypes had a poor survival rate. These findings recommended that patients with the GSTT1−/− genotype in COVID‐19 had a higher death rate. | 113 |