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Thread: Covid genetics and risk factors

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    Post Covid genetics and risk factors

    ACE2
    Studies have shown that rs2285666 correlates with hypertension, coronary heart disease and type 2 diabetes (Roach and Bugan, 2014; Asselta et al., 2020). This variant is more common among South Asians and East Asians and may help predict COVID-19 outcomes. It is possible that the effect of individual eQTLs is too small to affect the receptor function of ACE2.
    ACE2 splice region variant (rs2285666 C/T) that was significantly more prevalent among SARS-CoV-2 patients than the control population (p = 0.015). Further, intra-ethnic comparisons showed that this variant was more prevalent in inpatients (minor allele frequency (MAF) = 23.9%) compared to patients not hospitalised (MAF = 18.4%) within the European population (p = 0.029), suggesting it plays a role in susceptibility and severity. The ACE2 s2285666 and TMPRSS2 rs12329760 SNPs were significantly linked with COVID-19 disease severity, as were certain co-morbidities (hypertension, heart disease) and laboratory parameters. Both SNPs were amongst the highest predictors of disease severity: TMPRSS2 rs12329760 CT + TT [odds ratio (95% CI) 17.6 (5.1–61.10), ACE2 rs2285666 CT + TT 9.9 (3.2–30.9), both p < 0.001]. There was an increase in the expression of genotype frequencies of ACE2 rs2285666 and TMPRSS2 rs1232976 (TT), (CT + TT), and (T) allele in severe COVID-19 group compared to control and mild groups

    TMPRSS2 rs12329760 . Genotype frequencies TMPRSS2 (rs12329760) TT and CT + TT, and allele frequency T showed a significant increase in the severe COVID-19 group in the current study. Additionally, it was among the highest predictors of disease severity in logistic regression analysis, an observation that supports the hypotheses of Strope et al. (34) and Singh et al. (35) that these SNPs are directly pathogenic. The latter also suggest that sex may have a role in the pathogenicity of the TMPRSS2 SNPs, citing differences in gene responses to androgens, so being linked to sex polymorphism-specific effects, as TMPRSS2 is expressed in androgen-sensitive tissues, and to some extent, the weakly significant effect of sex on disease severity in our study may reflect this proposition. The current results showed a significant association of the TMPRSS2 rs12329760 (CT + TT) SNP with increased inflammatory marker CRP, and ferritin, LDH and D-Dimer. Iwata-Yoshikawa et al. (36) used a murine TMPRSS2 knock-out to speculate that the molecule (and by implication, its genotype variants) has a role in inflammatory responses to SARS-CoV. TMPRESS2 expression in the digestive tract (37) represents a route of viral entry; thus, certain SNPs may be related to gastrointestinal symptoms of the disease such as diarrhea.




    Two missense variants (K26R and N720D) were statistically more prevalent in the European population. The K26R increases the affinity of ACE2 for SARS-CoV-2, while N720D enhances TMPRSS2 activation and subsequent viral entry.

    The p. K26R variant was more common in Europeans (MAF = 0.710%) compared to South Asians (MAF = 0.275%; p < 0.001) and Africans (MAF = 0.155%; p = 0.001). The K26 residue lies on the proximal end of the SARS-CoV-2 RBD–ACE2 interface (Lan et al., 2020). Structural predictions have shown that the K26R variant enhances the affinity of ACE2 for SARS-CoV-2 by strengthening the hydrogen bond between H34 and Y453 of the S-protein (Stawiski et al., 2020; Al-Mulla et al., 2021).

    Variant p. N720D was also more common in Europeans (MAF = 2.64%) compared to South Asians (MAF = 0.609%; p < 0.001), Africans (MAF = 0.285%; p < 0.001) and East Asians (MAF = 0.198%; p < 0.001). The p. N720D variant lies in the C-terminal collectrin domain of ACE2. Although it is not involved in the SARS-CoV-2 S-protein interaction, studies have shown that it enhances transmembrane protease, serine 2 (TMPRSS2) binding and cleavage of ACE2. As TMPRSS2 cleavage of the ACE2 receptor increases viral entry, the p. N720D variant may lead to increased COVID-19 susceptibility (Mohammad et al., 2020; Al-Mulla et al., 2021).


    rs12006793 (d = 0.91) eQTL decreases ACE2 expression and was more common in the control group, suggesting it reduces COVID-19 risk. It was more common in Africans (MAF = 66.6%) and South Asians (MAF = 60.1%).

    the occurrence of specific comorbidities associated with renin–angiotensin system (RAS) imbalance mediated by the interaction between angiotensin-converting enzyme 2 (ACE2) and desintegrin and metalloproteinase domain 17 (ADAM17), along with specific genetic factors mainly associated with type II transmembrane serine protease (TMPRSS2) expression, could be decisive for the clinical outcome of COVID-19. key pathophysiological concepts related to the interplay between the angiotensin-converting enzyme 2 (ACE2), desintegrin and metalloproteinase domain 17 (ADAM17) and the type II transmembrane serine protease (TMPRSS2) in the major clinical disorders reported in COVID-19 patients. Another important mechanism to take into account, in this complex pathophysiological equation, is the ACE2 cytoplasmic tail cleavage mediated by TMPRSS2 (97). The cleavage of the ACE2 tail by TMPRSS2 increases viral uptake in target cells. More recently, a specific SARS-CoV-2 A2a subtype—mediated TMPRSS2 and MX1 genes up-regulation has been described in European and North American populations (22). These findings along with the higher TMPRSS2 expression on nasal epithelial cells from Black individuals than others races, may explain the higher rates of infection, and worse COVID-19 clinical outcomes observed in these populations, by the increasing TMPRSS2-mediated SARS-CoV-2 and ACE2 cleavage.



    APOE 2 and APOE 4 but not APOE3

    Two common single-nucleotide polymorphisms (SNPs) of the APOE gene: 388 T > C (rs429358) and 526C > T (rs7412). Three haplotypes (ɛ2(388 T–526 T), ɛ3(388 T-526C), ɛ4(388C-526C)) and six genotypes (ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4, ɛ4/ɛ4) can be formed by these SNPs [11]. Compared with ɛ3 homozygotes, patients with the ɛ2 allele have lower circulating total cholesterol (TC) levels and higher triglyceride levels, whereas those who carry the ɛ4 allele appear to have higher plasma levels of TC and LDL-C


    references

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    86.2 IRN_Shahr_I_Sokhta_BA2
    5.2 ITA_Sardinia_C_o:I15940 1.4 ITA_Daunian
    3.6 PAK_Saidu_Sharif_H
    3.6 VK2020_SWE_Gotland_VA:VK464

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    Table 2. Molecular pathways involved in SARS CoV 2 infection and pathway-based therapeutic targets.




    Signaling pathways Molecular targets Therapeutic agents Diseases Reference


    Renin-angiotensin system (RAS) pathway ACE2 NAAE (ACE2 inhibitor), rhACE2 (GSK2586881) SARS-CoV, ARDS [1], [2]

    TMPRSS2 Exogenous estrogen, Camostat mesylate, Aprotinin, MI-432, MI-1900, Nafamostat SARS-CoV-2 infection [3], [4]

    ACE Lisinopril, Enalapril, Vitamin D3 Heart/Kidney, Heart, Kidney, SARS-CoV-2 [5], [6]

    AT1R Losartan/Olmesartan, Losartan, Irbesartan, Telmisartan, Olmesartan Heart/Kidney, Aorta, Heart, Kidney, SARS-CoV-2 infection [5], [7]

    ADAM17 A1AT, TIMP-3, TAPI-1, siRNA, Apratastat, TMI-1 Chronic obstructive pulmonary disease, SARS-CoV-2 infection [8], [9], [10]

    IL-6-JAK/STAT IL-6 Sirukumab, FC-sgp130, Olokizumab, MAb 1339, CNTO328, Clazakizumab, Oroxylin A, ALX-0061, Siltuximab Cardiovascular disease, RA, Multiple myeloma, prostate cancer, Renal cell carcinoma, B-cell Non-Hodgkin lymphoma, Ovarian cancer, Non-small cell lung cancer, SARS-CoV-2 infection [11], [12], [13], [14]

    IL-6R Tocilizumab, Sarilumab, ERBF, SANT-7, sgp130FC, NRI Leukaemia, Metastatic breast cancer, Pancreatic cancer, RA, Multiple myeloma, tumor cell line [12], [15], [16], [17], [18]

    JAK TG101209, WP1066, CEP 3379, Sorafenib, Tofacitinib, Ruxolitinib, AG490 Lung cancer, Gastric cancer, Colorectal cancer, Glioblastoma, Cardiovascular disease, Pancreatic cancer [11], [19], [20], [21], [22], [23]

    gp130 B-P4, Madindoline A, SC144, Raloxifene, Bazedoxifene, LMT-28 Inflammatory hepatocellular adenoma, Non-small cell lung cancer xenograft, Ovarian cancer, Breast cancer, Erythroleukemia [24], [25], [26], [27], [28]

    JAK/STAT signaling Trichostatin A, Bufalin, Baricitinib, Ruxolitinib, Tofacitinib Experimental CRC, SARS-CoV-2 infection [29], [30]

    STAT3 JSI-124, Stattic, Eriocalyxin B, S3I-201, STA-21, OBP-31121, OBP-51602, AZD9150, C188–9 B-leukemia, Breast and liver cancer, prostate cancer, Cardiovascular disease, Hepatocellular carcinoma, Multiple myeloma, NHL, AML, ALL, CML, Nasopharyngeal carcinoma, Advanced solid tumors, Metastatic HNSCC, Advanced stage lymphomas, Advanced stage pancreatic cancer, NSCLC, CRC [11], [15], [31], [32], [33], [34], [35]

    SOCS3 SOCS3 Cardiovascular disease
    IL-1B signaling IL-1 Anakinra SARS-CoV-2 infection [30], [36]

    TNF signaling TNF-γ Baricitinib SARS-CoV-2 infection [36]

    TNF-α Adalimumab, Etanercept, Infliximab SARS-CoV-2 infection [36], [37], [38]

    TNF Infliximab, Golimumab, Adalimumab SARS-CoV-2 infection [30]

    IL-6 signaling IL-6 Tocilizumab, Sarilumab, Baricitinib SARS-CoV-2 infection [30], [36]

    IFN-γ signaling IFN-γ Emapalumab SARS-CoV-2 infection [30]

    IL-17 IL-17 Fedratinib, Secukinumab, Netakimab Myelofibrosis, SARS-CoV-2 infection [39], [40]

    GM-CSF GM-CSF Mavrilimumab, Lenzilumab, Tocilizumab SARS-CoV-2 infection [41]

    NF-κB signaling pathway Inhibit translocation of the RELA CAPE SARS-CoV [42], [43]

    Inhibit IKK complex Bay 11–7082, Parthenolide, Gabexate mesilate, resveratrol SARS-CoV, lipopolysaccharide (LPS)-induced tissue injury, allergic asthma [42], [44], [45], [46]

    Empty Cell NF-κB cascade Dexamethasone, Hydroxychloroquine, Macrolide antibiotics, N-acetylcysteine SARS-CoV-2 infection [47]

    TLR signaling pathway Inhibitor TLR3, TLR4, TLR7 and TLR8 Ulinastatin, M5049, Chloroquine, Hydroxychloroquine, Polyinosinic: polycytidylic acid, INNA-051 SARS-CoV-2 infection [48], [49], [50], [51], [52], [53], [54], [55]

    mTOR signaling pathway mTORC1 Sirolimus, Rapamycin, Azithromycin, Niclosamide SARS-CoV-2, H1N1, H3N2 [56], [57], [58], [59]

    mTOR Metformin, Buformin, Phenformin Influenza [57]

    P38 MAPK signaling pathway P38 Chloroquine, SB203580, Dilmapimod, Losmapimod HCoV-229E, Acute lung injury, Hypercholesterolemic patients [60], [61], [62]

    Kallikrein pathway B1R Safotibant reversion acute inflammatory pain induced by carrageenan, and persistent inflammatory pain induced by CFA [63]

    B2R Icatibant Hereditary angioedema, SARS-CoV-2 infection [64], [65]

    Kallikrein Lanadelumab,
    C1 esterase inhibitor Hereditary angioedema, SARS-CoV-2 infection [65], [66]

    HIF-1 signaling pathway HIF prolyl hydroxylase HIF prolyl hydroxylase inhibitors:
    FG-4592 (Roxadustat) SARS-CoV-2 infection [67]

    Cell death signaling pathway NLRP3 inflammasome MCC950, oridonin
    Ang (1–7) or heme oxygenase 1 activators Inflammatory diseases
    SARS-CoV-2 infection [68], [69]

    Inflammasome activation signaling Anakinra, Tocilizumab and IFN-β SARS-CoV-2 infection [69]

    RIPK3 and MLKL Zharp-99, necrosulfonamide, GSK843, GSK872 Inflammatory injury, cancer metastasis [70], [71]





    https://www.sciencedirect.com/scienc...53332221012063
    Yfull [B]ID: YF83218 Medals -> https://www.theapricity.com/forum/sh...-the-Deep-dive
    G25 Distance: 1.0778%
    86.2 IRN_Shahr_I_Sokhta_BA2
    5.2 ITA_Sardinia_C_o:I15940 1.4 ITA_Daunian
    3.6 PAK_Saidu_Sharif_H
    3.6 VK2020_SWE_Gotland_VA:VK464

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