Table 3.
Candidate genes, their polymorphisms and their association with COVID-19 severity and susceptibility in select populations
| Gene | Polymorphism | Population | Sample size | Implication | Reference |
|---|---|---|---|---|---|
| 3p21.31 cluster | rs11385942 | Spain and Italy | 1980 | The 3p21.31 cluster was observed in patients with respiratory failure. | (The Severe Covid-19 GWAS Group, 2020) |
| Androgen receptor | Not mentioned | European males | 1178 | Androgen receptors with shorter polyQ alleles offered protection against severe COVID-19 in Italian males. | (Baldassarri et al., 2021) |
| BPIFB4 | LAV-BPIFB4 | Italy | 171, 64 with COVID-19 | Values of BPIFB4 were markedly lower in COVID-19-positive individuals as compared with negative patients. BPIFB4 levels in plasma are negatively correlated with SARS-CoV-2 illness severity. |
(Ciaglia et al., 2021) |
| Complement 3 | Complement 3 (S) | European, Mediterranean, and the Middle East | Not mentioned | C3 was associated with increased COVID-19-related death. | (Delanghe et al., 2021) |
| CCR5 | rs9845542, rs12639314, rs35951367, rs34418657 | Europe | 6406 hospitalized COVID-19 patients and 902,088 controls | rs9845542, rs12639314, rs35951367 polymorphisms were associated with severe COVID-19 illness and low CCR5 expression | (Cantalupo et al., 2021) |
| CCR5 | rs333 | Czech Republic | 416 | Δ32 deletion in the CCR5, most found in Caucasians, could offer protection against COVID-19 illness. | (Hubacek et al., 2021) |
| TLL-1 | rs4618569 | Egypt | 141 patients, 100 controls | The A allele of the TLL-1 rs17047200 variant is associated with poor clinical outcomes. | (Agwa et al., 2021) |
| GOLGA3, DPP7, TMPRSS2 | rs12329760 in TMPRSS2 | China | 332 | The rs12329760 variant in TMPRSS2 was less prevalent in severe SARS-CoV-2 patients. Loss of function mutation in DPP7 and GOLGA3 was observed in severe COVID-19 disease. |
(Wang et al., 2020) |
| IFI30 | rs11554159 | Spain and Italy | N/A | IFI30 polymorphisms may be a risk factor to acquiring severe COVID-19 disease | (Monticelli et al., 2021) |
| MEFV | rs3743930 | Spain and Italy | N/A | Deleterious variants in MEFV could affect the severity of COVID-19. | (Monticelli et al., 2021) |
| IFITM3 | rs12252, rs34481144 | Germany | 239 patients with COVID-19 and 253 controls. | There was no association between these polymorphisms and severity of COVID-19 illness. | (Schönfelder et al., 2021) |
| IFITM3 | rs12252 | China | 80 | Presence of the rs12252 variant of the IFITM3 correlated with a more critical COVID-19 infection. | (Zhang et al., 2020) |
| LZTFL1, XCR1, CCR9, FYCO1, SLC6A20, CXCR6, HNRNPK, RMI1, IFNAR2, ABO | rs9976829 in IFNAR2- IL10RB | Italy and Spain | 1,610 COVID-19 patients and 2,205 controls | All genes were strongly associated with risk of SARS-CoV-2 infection. A 16% higher chance of having SARS-CoV-2 in subjects with the G allele of rs9976829. |
(Ma et al., 2021) |
| MBL2 | rs1800450 | N/A | 284 patients, 100 control | Reduced MBL2 levels correlated with a more severe COVID-19 clinical course. | (Medetalibeyoglu et al., 2021) |
| MUC5B | rs35705950 | Europe | 4124 cases and 20,465 controls | rs35705950 offered protection against COVID-19 in patients with pulmonary fibrosis. | (Fadista et al., 2021) |
| PNPLA3, TLL-1 | PNPLA3 rs738409, TLL-1 rs17047200, | Italy | 383 | Polymorphisms of PNPLA3 and TLL-1 were markedly associated with severe COVID-19 disease and worse outcomes. | (Grimaudo et al., 2021) |
| TAS2R38 | Not mentioned | USA | 1935, 265 tested positive | T2Rs may protect against illness by SARS-CoV-2. | (Barham et al., 2021) |
| DDR1 | rs17047200 | Egypt | 141 patients, 100 controls | The AG genotype of the DDR1 rs4618569is associated with poor outcomes in COVID-19 patients. | (Agwa et al., 2021) |
| TLR3 | rs3775291 | Spain and Italy | N/A | A missense mutation in TLR3 (rs3775291) is associated with severe disease. | (Monticelli et al., 2021) |
| TLR7 | rs189681811, rs147244662, rs149314023, rs200146658, rs5743781 | Italy | 79 cases, 77 controls |
TLR7 variants were found in 2.1% of males with severe disease, while none were found in asymptomatic males. Lower TLR7 expression was observed in COVID-19 patients. |
(Fallerini et al., 2021) |
| TMPRSS2 | rs2298659, rs17854725, rs12329760, rs3787950 | Italy | 3984 | Exonic variant (p.Val160Met) and two haplotypes in TMPRSS2 showed substantial disparities between East Asians and Italians, showing increased levels of TMPRSS2 in Italians, leading to increased susceptibility to infection. | (Asselta et al., 2020) |
| TMPRSS2 | N/A | Africa | N/A | Genetic variants in TMPRSS2 may alter an individual’s variability in susceptibility to COVID-19 infection and disease severity. | (Ortiz-Fernández and Sawalha, 2020) |
| TNFRSF1A | rs767455 | Mexico | 102 patients, 25 controls | This polymorphism is associated with increased COVID-19 disease severity. | (Palacios et al., 2021) |
| TNFRSF13C | p.His159Tyr | Italy | 500 | p.His159Tyr variant of TNFRSF13C was notably increased in patients with severe illness compared to asymptomatic patients. | (Russo et al., 2021) |
| Vitamin D (DHCR7/NADSYN1), CYP2R1 | Vitamin D (DHCR7/NADSYN1) rs12785878, CYP2R1 rs10741657 | Serbia | 120 males | The presence of CYP2R1 and DHCR7/NADSYN1 correlated with COVID-19 increased illness severity in adults. | (Kotur et al., 2021) |
| IFNλ3 | rs12979860, rs8099917, rs12980275 | Iran | 750 patients with COVID-19 | Frequency of these favorable variants was significantly higher in patients who survived from COVID-19 infection. | (Rahimi et al., 2021) |
| IFNλ4 | rs368234815 | Iran | 750 COVID-19 positive patients | Higher frequency of this variant was present in patients who survived from COVID-19 infection. | (Rahimi et al., 2021) |
| TMPRSS2 | rs2070788 | India | 393 COVID-19 patients | rs2070788 may lead to worse clinical outcomes in COVID-19 patients. | (Pandey et al., 2022) |
| TIRAP | rs8177374 | Netherlands | 116 COVID-19 patients | Carriers of rs8177374 could be associated with a significantly lower COVID-19 mortality. | (Traets et al., 2022) |
| TMPRSS2 | rs17854725/rs75603675/rs12329760/rs4303795 | Iran | 288 COVID-19 patients | These polymorphisms were associated with increased risk of COVID-19 infection and severe disease. | (Rokni et al., 2022) |
| IL-6 | rs1800795, rs1800796, rs1800797 | Iran | 175 COVID-19 patients, 171 controls | No significant differences in severity of COVID-19 disease in patients with these polymorphisms. | (Falahi et al., 2022) |
| TMPRSS2/MX1 (21q22.3) locus | rs3787946, rs9983330, rs12329760, rs2298661, rs9985159 | Italy | 6,406 COVID-19 patients, 902,088 controls | These polymorphisms showed an association with severe COVID-19 disease. | (Andolfo et al., 2021) |
BPIFB4: BPI fold containing family B member 4, CCR5: CC motif chemokine receptor 5, CCR9: CC motif chemokine receptor 9, CXCR6: C-X motif chemokine receptor 6, DPP7: dipeptidyl peptidase 7, DDR1: discoidin domain receptor tyrosine kinase 1, GOLGA3: Golgin A3, TMPRSS2: transmembrane protease, serine 2, IFI30: gamma-interferon-inducible lysosomal thiol reductase, SLC6A20: solute carrier family 6 member 20, LZTFL1: human leucine zipper transcription factor like 1, XCR1: X-C motif chemokine receptor 1, FYCO1: fyve and coiled-coil domain-containing protein 1, TLR3: toll like receptor 3, TLR7: toll like receptor 7, IFNAR2: interferon alpha and beta receptor subunit 2, IFNλ3: interferon lambda 3, IFNλ3: interferon lambda 3, MUC5B: mucin 5B, HNRNPK: heterogeneous nuclear ribonucleoprotein K, IFITM3: interferon induced transmembrane protein 3, RMI1: RecQ mediated genome instability 1, MBL2: mannose binding lectin 2, PNPLA3: patatin-like phospholipase domain-containing protein 3, TLL1: tolloid like 1, TAS2R38: taste receptor 2 member 38, TNFRSF13C: TNF receptor superfamily member 13C, TNFRSF1A: TNF receptor superfamily member 1A, CYP2R1: cytochrome P450 gamily 2 subfamily R member 1, TIRAP: TIR Domain Containing Adaptor Protein