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2.
Am J Respir Crit Care Med ; 206(10): 1220-1229, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2138355

ABSTRACT

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.


Subject(s)
COVID-19 , Idiopathic Pulmonary Fibrosis , Humans , COVID-19/epidemiology , COVID-19/genetics , Mucin-5B/genetics , Polymorphism, Genetic , Idiopathic Pulmonary Fibrosis/genetics , Genotype , Hospitalization , Genetic Predisposition to Disease/genetics
3.
Int J Mol Sci ; 23(21)2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2118407

ABSTRACT

Longevity is a unique human phenomenon and a highly stable trait, characterized by polygenicity. The longevity phenotype occurs due to the ability to successfully withstand the age-related genomic instability triggered by Alu elements. The purpose of our cross-sectional study was to evaluate the combined contribution of ACE*Ya5ACE, CDH4*Yb8NBC516, COL13A1*Ya5ac1986, HECW1*Ya5NBC182, LAMA2*Ya5-MLS19, PLAT*TPA25, PKHD1L1*Yb8AC702, SEMA6A*Yb8NBC597, STK38L*Ya5ac2145 and TEAD1*Ya5ac2013 Alu elements to longevity. The study group included 2054 unrelated individuals aged from 18 to 113 years who are ethnic Tatars from Russia. We analyzed the dynamics of the allele and genotype frequencies of the studied Alu polymorphic loci in the age groups of young (18-44 years old), middle-aged (45-59 years old), elderly (60-74 years old), old seniors (75-89 years old) and long-livers (90-113 years old). Most significant changes in allele and genotype frequencies were observed between the long-livers and other groups. The search for polygenic predictors of longevity was performed using the APSampler program. Attaining longevity was associated with the combinations LAMA2*ID + CDH4*D (OR = 2.23, PBonf = 1.90 × 10-2) and CDH4*DD + LAMA2*ID + HECW1*D (OR = 4.58, PBonf = 9.00 × 10-3) among persons aged between 18 and 89 years, LAMA2*ID + CDH4*D + SEMA6A*I for individuals below 75 years of age (OR = 3.13, PBonf = 2.00 × 10-2), LAMA2*ID + HECW1*I for elderly people aged 60 and older (OR = 3.13, PBonf = 2.00 × 10-2) and CDH4*DD + LAMA2*D + HECW1*D (OR = 4.21, PBonf = 2.60 × 10-2) and CDH4*DD + LAMA2*D + ACE*I (OR = 3.68, PBonf = 1.90 × 10-2) among old seniors (75-89 years old). The key elements of combinations associated with longevity were the deletion alleles of CDH4 and LAMA2 genes. Our results point to the significance for human longevity of the Alu polymorphic loci in CDH4, LAMA2, HECW1, SEMA6A and ACE genes, involved in the integration systems.


Subject(s)
Longevity , Polymorphism, Genetic , Adolescent , Adult , Aged , Aged, 80 and over , Humans , Middle Aged , Young Adult , Alu Elements/genetics , Cross-Sectional Studies , Gene Frequency , Genotype , Longevity/genetics , Nerve Tissue Proteins/genetics , Peptidyl-Dipeptidase A/genetics , Ubiquitin-Protein Ligases/genetics , Gene Deletion
4.
Dis Markers ; 2022: 5988976, 2022.
Article in English | MEDLINE | ID: covidwho-2113116

ABSTRACT

Several studies have discovered a relationship between specific blood types, genetic variations of the ABO gene, and coronavirus disease 2019 (COVID-19). Therefore, the aim of this study was to evaluate the association between ABO rs657152 polymorphisms and ABO blood groups with COVID-19 mortality. The tetraprimer amplification refractory mutation system, polymerase chain reaction method, was used for ABO rs657152 polymorphism genotyping in 1,211 dead and 1,442 improved patients. In the current study, the frequency of ABO rs657152 AA than CC genotypes was significantly higher in dead patients than in improved patients. Our findings indicated that blood type A was associated with the highest risk of COVID-19 mortality compared to other blood groups, and patients with blood type O have a lower risk of infection, suggesting that blood type O may be a protective factor against COVID-19 mortality. Multivariate logistic regression test indicated that higher COVID-19 mortality rates were linked with alkaline phosphatase, alanine aminotransferase, high density lipoprotein, low-density lipoprotein, fasting blood glucose, uric acid, creatinine, erythrocyte sedimentation rate, C-reactive protein, 25-hydroxyvitamin D, real-time PCR Ct values, ABO blood groups, and ABO rs657152 AA genotype. In conclusion, the AA genotype of ABO rs657152 and blood type A were associated with a considerably increased frequency of COVID-19 mortality. Further research is necessary to validate the obtained results.


Subject(s)
ABO Blood-Group System , COVID-19 , Humans , ABO Blood-Group System/genetics , Iran/epidemiology , COVID-19/genetics , Genotype , Polymorphism, Genetic
6.
Transbound Emerg Dis ; 69(5): e3336-e3345, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2053027

ABSTRACT

Canine babesiosis caused by Babesia canis (Piana & Galli-Valerio, 1895) is emerging in new regions in Europe since its vector Dermacentor reticulatus (Fabricius, 1794) is expanding its geographic range. In the Berlin/Brandenburg area in northeast Germany, D. reticulatus is highly abundant but in the past only one autochthonous B. canis infection was reported. Since 2015, autochthonous cases were occasionally diagnosed but numbers increased since autumn 2019. The aim of the study was to genotype autochthonous canine Babesia spp. infections from Berlin/Brandenburg. Between 04/2015 and 01/2022, 46 dogs with acute babesiosis were presented to the small animal clinic (one dog was infected twice resulting in 47 samples). There were 32 dogs that had never left Berlin/Brandenburg and 14 others that had not left the region in the 6 weeks prior to disease onset. PCRs targeting the 18S rRNA and the Bc28.1 merozoite surface antigen were positive in 47 and 42 samples, respectively. Sequencing of cloned PCR products identified all samples as B. canis with 17 18S rRNA and 12 Bc28.1 haplotypes. Based on network analysis for 18S rRNA sequences and a previously described polymorphic dinucleotide, samples were assigned to two distinct clusters. One contained 31 and the other 16 samples. Using network analysis, the Bc28.1 haplotypes could also be separated into two clusters differing by at least five polymorphisms. Analyses of sequences from multiple clones indicated the presence of up to five 18S rRNA and eight Bc28.1 haplotypes and thus high parasite variability in an individual host. The genetic diversity could suggest that the parasites in the region have multiple origins, but diversity in individual dogs and dog populations from endemic regions is unknown. The suitability of both markers for genotyping is questionable due to potential intragenomic diversity for the rRNA and high intergenomic variability for the Bc28.1 marker.


Subject(s)
Babesia , Babesiosis , Dermacentor , Dog Diseases , Animals , Antigens, Surface , Babesia/genetics , Babesiosis/epidemiology , Babesiosis/parasitology , Berlin , Dermacentor/parasitology , Disease Outbreaks/veterinary , Dog Diseases/epidemiology , Dog Diseases/parasitology , Dogs , Germany/epidemiology , Polymorphism, Genetic , RNA, Ribosomal, 18S/genetics
7.
Mol Genet Genomic Med ; 10(11): e2063, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2047838

ABSTRACT

BACKGROUND: ACE1 I/D rs1799752 and ACE2 rs2285666 genetic polymorphisms could play a critical role in altering the clinical outcomes of SARS-CoV-2. The findings of previous studies remained inconclusive. This meta-analysis was performed to evaluate the association and provide a more reliable outcome. METHODS: This study was completed following the updated recommendations of PRISMA using RevMan 5.4.1 statistical software. RESULTS: A total of 11 studies with 950 severe cases and 1573 non-severe cases with COVID-19 infection were included. Pooled analysis showed that ACE1 I/D polymorphism was correlated with the severity of SARS-CoV-2 in the DD genotype and D allele for the fixed-effects model (OR:1.27 and OR:1.17). Besides, codominant 3, recessive, and allele models were associated with the severity of the fixed-effects model (OR:1.35, OR:1.37, and OR:1.20) in Caucasian ethnicity. ACE2 rs2285666 was linked with the severity in codominant 3 (OR:2.63, for both random- and fixed effects-models), overdominant (OR:1.97, for random-effects model and OR:1.97, for fixed effects-model), and recessive model (OR:0.41 for fixed- and random-effects model). Allele model of rs2285666 showed a significant association in the fixed-effects model (OR:1.61). CONCLUSION: Our present meta-analysis suggests that ACE1 I/D rs1799752 and ACE2 rs2285666 variants may enhance the severity in SARS-CoV-2 infected patients. Future studies are warranted to verify our findings.


Subject(s)
COVID-19 , Humans , COVID-19/genetics , Angiotensin-Converting Enzyme 2/genetics , SARS-CoV-2 , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic
8.
Clin Chim Acta ; 536: 39-44, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2031181

ABSTRACT

BACKGROUND: Coronavirus disease 2019(COVID-19), the infectious respiratory disease caused by a newly discovered pathogen (severe acute respiratory syndrome coronavirus 2), is a pandemic that places a burden on the health care system. Recently, most research on COVID-19 has emphasized its profound impact on specific regions and ethnic groups. A possible explanation for these variations in disease presentation and severity might be differences in the gene pool of populations. This study therefore attempted to clarify possible involvements of genetic factors affecting COVID-19 pathogenesis with a focus on voltage-gated potassium channel-interacting protein 4 (KCNIP4) and angiotensin-converting enzyme 1 (ACE1) gene polymorphisms. MATERIALS AND METHODS: In this case-control study, the polymorphisms were genotyped using PCR in 194 COVID-19 patients and 194 healthy controls. RESULTS: COVID-19 susceptibility and severity appeared to be unaffected by these polymorphisms. However, this study supported the relevance of ACE1 II genotype frequency to a decreased number of deaths due to the infection. We found that COVID-19 patients with the ACE1 II genotype have a statistically significant better chance of survival (p = 0.008). CONCLUSION: This study strengthens the idea that the ACE1 I/D polymorphism can be a novel prognostic factor indicating the outcome of COVID-19.


Subject(s)
COVID-19 , Potassium Channels, Voltage-Gated , Angiotensin-Converting Enzyme 2 , Angiotensins/genetics , Angiotensins/metabolism , COVID-19/genetics , Case-Control Studies , Humans , Iran , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Polymorphism, Genetic , Potassium Channels, Voltage-Gated/genetics
9.
Int J Environ Res Public Health ; 19(15)2022 08 07.
Article in English | MEDLINE | ID: covidwho-1994073

ABSTRACT

Brain-Derived Neurotropic Factor (BDNF) is one of the essential mediating factors of exercise-induced neuroplasticity, but the underlying molecular mechanisms of exercise-induced neuroplasticity are still largely unknown. Personality dimensions differentiate individuals and depend on genes and environmental factors. The dimensions of openness to experience, emotional stability, extraversion and conscientiousness have been reported to be positively related to performance; considering agreeableness, a negative relation with sports performance was emphasized. However, not enough effort has been put into investigating the relationship between genetic polymorphisms affecting psychological abilities and competitive power sports. The aim of this study was to investigate the association of the rs6265 polymorphism of BDNF with personality dimensions in martial arts athletes. The study was conducted among martial arts athletes. The study group included 258 volunteers (martial arts athletes (n = 106) and controls (n = 152). BDNF polymorphism testing was performed using the real-time PCR method; personality dimensions were assessed using standardized NEO-FFI questionnaires. All analyses were performed using STATISTICA 13. We observed that martial arts athletes' G/G genotypes compared to the control group G/G genotypes presented significantly higher severity of personality dimension "conscientiousness". In comparison with the controls, the case group subjects had significantly higher scores in the dimension extraversion (M 6.89 vs. M 6.43, p = 0.0405) and conscientiousness/scale (M 7.23 vs. M 5.89, p < 0.0001). The results of 2 × 3 factorial ANOVA noticed a statistically significant effect of combined factor BDNF rs6265 genotype of martial arts/control (F2,252 = 3.11, p = 0.0465, η2 = 0.024). Additionally, we observed that the results of 2 × 3 factorial ANOVA showed a statistically significant influence of combined factor BDNF rs6265 of genotype martial arts/ control (F2,252 = 6.16, p = 0.0024, η2 = 0.047). The combination of the analysis of personality dimensions with genetics-as in the case of the polymorphism of the BDNF gene related to neuroplasticity-indicates that neurobiology cannot be ignored in educating sports champions. We already know that this is related to genetics. However, little is still known about the influence of personality traits on sports performance. We observed that martial arts athletes' G/G genotypes, in comparison to the control group's G/G genotypes, presented significantly higher severity of personality dimension "conscientiousness". This is worthy of further analysis and probably longitudinal studies on a more numerous group of athletes.


Subject(s)
Athletes , Brain-Derived Neurotrophic Factor , Brain , Brain-Derived Neurotrophic Factor/genetics , Humans , Personality/genetics , Polymorphism, Genetic
10.
Genes (Basel) ; 13(7)2022 06 21.
Article in English | MEDLINE | ID: covidwho-1963782

ABSTRACT

The proposed SARS-CoV-2-induced dysregulation of the renin-angiotensin-aldosterone (RAAS) system results in endothelial dysfunction and microvascular thrombosis. The retinal plexuses contain terminal vessels without anastomotic connections, making the retina especially susceptible to ischemia. This study aimed to determine the role of selected polymorphisms of genes in the RAAS pathway in COVID-19 severity and their association with the presence of COVID-19 retinopathy. 69 hospitalized patients in the acute phase of COVID-19 without known systemic comorbidities and 96 healthy controls were enrolled in this prospective cross-sectional study. The retina was assessed with fundus photography using a Topcon DRI OCT Triton (Topcon Corp., Tokyo, Japan) in the COVID-19 unit. Genotyping of selected polymorphisms in the genes for ACE (rs4646994), ACE2 (rs2285666), and AGTR2 (rs1403543) was performed. The COVID-19 group was divided into mild (n = 12) and severe (n = 57), and then further divided according to the presence of COVID-19 retinopathy (Yes, n = 50; No, n = 19). The presence of the AGTR2 rs1403543-AA genotype was associated with a 3.8-fold increased risk of COVID-19 retinopathy (p = 0.05). The genotype frequencies of selected gene polymorphisms were not significantly associated with either the presence of COVID-19 or its severity. This is the first study demonstrating a borderline association of the AGTR2 rs1403543-AA genotype with COVID-19 retinopathy in males; hence, the AGTR2 rs 1403543 A allele might represent a genetic risk factor for COVID-19 retinopathy in males.


Subject(s)
COVID-19 , Retinal Diseases , Angiotensin-Converting Enzyme 2/genetics , COVID-19/complications , COVID-19/genetics , Cross-Sectional Studies , Humans , Male , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Polymorphism, Genetic , Prospective Studies , Receptor, Angiotensin, Type 2 , Retinal Diseases/genetics , SARS-CoV-2
11.
Hum Mol Genet ; 31(23): 3945-3966, 2022 Nov 28.
Article in English | MEDLINE | ID: covidwho-1948292

ABSTRACT

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.


Subject(s)
COVID-19 , Humans , COVID-19/genetics , SARS-CoV-2/genetics , Genome-Wide Association Study , Haplotypes , Polymorphism, Genetic
12.
Microbiol Spectr ; 10(4): e0087022, 2022 08 31.
Article in English | MEDLINE | ID: covidwho-1938015

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 have a single envelope glycoprotein (S protein) that binds to human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. Previous mutational scanning studies have suggested that some substitutions corresponding to single nucleotide variants (SNVs) in human ACE2 affect the binding affinity to the receptor binding domain (RBD) of the SARS-CoV-2 S protein. However, the importance of these substitutions in actual virus infection is still unclear. In this study, we investigated the effects of the reported ACE2 SNV substitutions on the entry of SARS-CoV and SARS-CoV-2 into cells, using vesicular stomatitis Indiana virus (VSIV) pseudotyped with S proteins of these coronaviruses (CoVs). HEK293T cells transfected with plasmids expressing ACE2 having each SNV substitution were infected with the pseudotyped VSIVs and relative infectivities were determined compared to the cells expressing wild-type ACE2. We found that some of the SNV substitutions positively or negatively affected the infectivities of the pseudotyped viruses. Particularly, the H505R substitution significantly enhanced the infection with the pseudotyped VSIVs, including those having the substitutions found in the S protein RBD of SARS-CoV-2 variants of concern. Our findings suggest that human ACE2 SNVs may potentially affect cell susceptibilities to SARS-CoV and SARS-CoV-2. IMPORTANCE SARS-CoV and SARS-CoV-2 are known to cause severe pneumonia in humans. The S protein of these CoVs binds to the ACE2 molecule on the plasma membrane and mediates virus entry into cells. The interaction between the S protein and ACE2 is thought to be important for host susceptibility to these CoVs. Although previous studies suggested that some SNV substitutions in ACE2 might affect the binding to the S protein, it remains elusive whether these SNV substitutions actually alter the efficiency of the entry of SARS CoVs into cells. We analyzed the impact of the ACE2 SNVs on the cellular entry of SARS CoVs using pseudotyped VSIVs having the S protein on the viral surface. We found that some of the SNV substitutions positively or negatively affected the infectivities of the viruses. Our data support the notion that genetic polymorphisms of ACE2 may potentially influence cell susceptibilities to SARS CoVs.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , HEK293 Cells , Humans , Polymorphism, Genetic , Protein Binding , Receptors, Virus/genetics , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus
13.
PLoS One ; 17(7): e0270627, 2022.
Article in English | MEDLINE | ID: covidwho-1923710

ABSTRACT

Although advanced age and presence of comorbidities significantly impact the variation observed in the clinical symptoms of COVID-19, it has been suggested that genetic variants may also be involved in the disease. Thus, the aim of this study was to perform a systematic review with meta-analysis of the literature to identify genetic polymorphisms that are likely to contribute to COVID-19 pathogenesis. Pubmed, Embase and GWAS Catalog repositories were systematically searched to retrieve articles that investigated associations between polymorphisms and COVID-19. For polymorphisms analyzed in 3 or more studies, pooled OR with 95% CI were calculated using random or fixed effect models in the Stata Software. Sixty-four eligible articles were included in this review. In total, 8 polymorphisms in 7 candidate genes and 74 alleles of the HLA loci were analyzed in 3 or more studies. The HLA-A*30 and CCR5 rs333Del alleles were associated with protection against COVID-19 infection, while the APOE rs429358C allele was associated with risk for this disease. Regarding COVID-19 severity, the HLA-A*33, ACE1 Ins, and TMPRSS2 rs12329760T alleles were associated with protection against severe forms, while the HLA-B*38, HLA-C*6, and ApoE rs429358C alleles were associated with risk for severe forms of COVID-19. In conclusion, polymorphisms in the ApoE, ACE1, TMPRSS2, CCR5, and HLA loci appear to be involved in the susceptibility to and/or severity of COVID-19.


Subject(s)
COVID-19 , Genetic Predisposition to Disease , Apolipoproteins E , COVID-19/genetics , HLA-A Antigens , Humans , Polymorphism, Genetic
14.
Drug Metab Dispos ; 50(9): 1151-1160, 2022 09.
Article in English | MEDLINE | ID: covidwho-1923099

ABSTRACT

Molnupiravir is one of the two coronavirus disease 2019 (COVID-19) oral drugs that were recently granted the emergency use authorization by the Food and Drug Administration (FDA). Molnupiravir is an ester and requires hydrolysis to exert antiviral activity. Carboxylesterases constitute a class of hydrolases with high catalytic efficiency. Humans express two major carboxylesterases (CES1 and CES2) that differ in substrate specificity. Based on the structural characteristics of molnupiravir, this study was performed to test the hypothesis that molnupiravir is preferably hydrolyzed by CES2. Several complementary approaches were used to test this hypothesis. As many as 24 individual human liver samples were tested and the hydrolysis of molnupiravir was significantly correlated with the level of CES2 but not CES1. Microsomes from the intestine, kidney, and liver, but not lung, all rapidly hydrolyzed molnupiravir and the magnitude of hydrolysis was related closely to the level of CES2 expression among these organs. Importantly, recombinant CES2 but not CES1 hydrolyzed molnupiravir, collectively establishing that molnupiravir is a CES2-selective substrate. In addition, several CES2 polymorphic variants (e.g., R180H) differed from the wild-type CES2 in the hydrolysis of molnupiravir. Molecular docking revealed that wild-type CES2 and its variant R180H used different sets of amino acids to interact with molnupiravir. Furthermore, molnupiravir hydrolysis was significantly inhibited by remdesivir, the first COVID-19 drug granted the full approval by the FDA. The results presented raise the possibility that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations and warrants further investigation. SIGNIFICANCE STATEMENT: COVID-19 remains a global health crisis, and molnupiravir is one of the two recently approved oral COVID-19 therapeutics. In this study, we have shown that molnupiravir is hydrolytically activated by CES2, a major hydrolase whose activity is impacted by genetic polymorphic variants, disease mediators, and many potentially coadministered medicines. These results presented raise the possibility that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations and warrants further investigation.


Subject(s)
COVID-19 , COVID-19/drug therapy , Carboxylesterase/metabolism , Carboxylic Ester Hydrolases/metabolism , Cytidine/analogs & derivatives , Drug Interactions , Humans , Hydrolysis , Hydroxylamines , Molecular Docking Simulation , Pharmaceutical Preparations/metabolism , Polymorphism, Genetic
15.
Int J Mol Sci ; 23(13)2022 Jun 23.
Article in English | MEDLINE | ID: covidwho-1917513

ABSTRACT

The SARS-CoV-2 disease presents different phenotypes of severity. Comorbidities, age, and being overweight are well established risk factors for severe disease. However, innate immunity plays a key role in the early control of viral infections and may condition the gravity of COVID-19. Natural Killer (NK) cells are part of innate immunity and are important in the control of virus infection by killing infected cells and participating in the development of adaptive immunity. Therefore, we studied the short tandem repeat (STR) transmembrane polymorphisms of the major histocompatibility complex class I chain-related A (MICA), an NKG2D ligand that induces activation of NK cells, among other cells. We compared the alleles and genotypes of MICA in COVID-19 patients versus healthy controls and analyzed their relation to disease severity. Our results indicate that the MICA*A9 allele is related to infection as well as to symptomatic disease but not to severe disease. The MICA*A9 allele may be a risk factor for SARS-CoV-2 infection and symptomatic disease.


Subject(s)
COVID-19 , Histocompatibility Antigens Class I , COVID-19/genetics , COVID-19/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Major Histocompatibility Complex , Polymorphism, Genetic , SARS-CoV-2/immunology
16.
J Popul Ther Clin Pharmacol ; 29(1): e122-e141, 2022.
Article in English | MEDLINE | ID: covidwho-1893735

ABSTRACT

It has been a busy year for coronaviruses, with the most recent one causing severe coronavirus illness in 2019 (COVID-19). It is broadly distributed in many human tissues and organs as the potential SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2). ACE2 provides homeostatic modulation of circulation angiotensin II levels by acting as a physiological counterbalance to ACE. They have been linked to COVID-19 disease acquisition, progression, and severity. As a result, we investigated how ACE2 variations and epigenetic variables affect SARS-CoV-2 infection susceptibility and infection outcomes in terms of age, gender, and ethnicity. Debates raged over the etiology of this occurrence. It is important to note that further research is required to demonstrate the efficacy of human recombinant ACE2 and ACE2-derived peptides in fighting SARSCoV-2 variants. Better recognition of a host genetic, as well as the function of the properties of ACE2 variations, would assist in explaining clinical disparities of infection between individuals and contribute to the development of remedies and managing future SARS-CoV-2 epidemics, an essential function for ACE2 in essential hypertension (EH). We wanted to see how ACE2 gene polymorphisms and enzyme activity correlated with COVID-19 incidence in the Iraqi province of Al-Diwaniya. A total of 63 COVID-19 patients and 70 (NT) controls were genotyped using Sequenom Mass-ARRAY RS1000 for ACE2. Participants' ACE2 rs1514283 SNP was linked to COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19 , COVID-19/genetics , Humans , Incidence , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic , SARS-CoV-2
17.
Gene ; 836: 146674, 2022 Aug 20.
Article in English | MEDLINE | ID: covidwho-1885774

ABSTRACT

BACKGROUND: COVID-19 is associated with several risk factors such as distinct ethnicities (genetic ancestry), races, sexes, age, pre-existing comorbidities, smoking, and genetics. The authors aim to evaluate the correlation between variability in the host genetics and the severity and susceptibility towards COVID-19 in this study. METHODS: Following the PRISMA guidelines, we retrieved all the relevant articles published until September 15, 2021, from two online databases: PubMed and Scopus. FINDINGS: High-risk HLA haplotypes, higher expression of ACE polymorphisms, and several genes of cellular proteases such as TMPRSS2, FURIN, TLL-1 increase the risk of susceptibility and severity of COVID-19. In addition, upregulation of several genes encoding for both innate and acquired immune systems proteins, mainly CCR5, IFNs, TLR, DPPs, and TNF, positively correlate with COVID-19 severity. However, reduced expression or polymorphisms in genes affecting TLR and IFNλ increase COVID-19 severity. CONCLUSION: Higher expression, polymorphisms, mutations, and deletions of several genes are linked with the susceptibility, severity, and clinical outcomes of COVID-19. Early treatment and vaccination of individuals with genetic predisposition could help minimize the severity and mortality associated with COVID-19.


Subject(s)
COVID-19 , COVID-19/genetics , Genetic Predisposition to Disease , Haplotypes , Humans , Polymorphism, Genetic , SARS-CoV-2
18.
Endocrinol Metab (Seoul) ; 37(3): 392-407, 2022 06.
Article in English | MEDLINE | ID: covidwho-1875844

ABSTRACT

Vitamin D has received considerable optimistic attention as a potentially important factor in many pathological states over the past few decades. However, the proportion of the active form of vitamin D metabolites responsible for biological activity is highly questionable in disease states due to flexible alterations in the enzymes responsible for their metabolism. For instance, CYP3A4 plays a crucial role in the biotransformation of vitamin D and other drug substances. Food-drug and/or drug-drug interactions, the disease state, genetic polymorphism, age, sex, diet, and environmental factors all influence CYP3A4 activity. Genetic polymorphisms in CYP450-encoding genes have received considerable attention in the past few decades due to their extensive impact on the pharmacokinetic and dynamic properties of drugs and endogenous substances. In this review, we focused on CYP3A4 polymorphisms and their interplay with vitamin D metabolism and summarized the role of vitamin D in calcium homeostasis, bone diseases, diabetes, cancer, other diseases, and drug substances. We also reviewed clinical observations pertaining to CYP3A4 polymorphisms among the aforementioned disease conditions. In addition, we highlighted the future perspectives of studying the pharmacogenetics of CYP3A4, which may have potential clinical significance for developing novel diagnostic genetic markers that will ascertain disease risk and progression.


Subject(s)
Endocrine System Diseases , Neoplasms , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Endocrine System Diseases/genetics , Humans , Neoplasms/genetics , Pharmacogenetics , Polymorphism, Genetic , Vitamin D
19.
Medicine (Baltimore) ; 101(21): e29405, 2022 May 27.
Article in English | MEDLINE | ID: covidwho-1874049

ABSTRACT

BACKGROUND: Corona virus disease 2019 (COVID-19) is caused by SARS-CoV-2, the pathogenic process of SARS-Cov-2 is related to the angiotensin-2 converting enzyme (ACE-2) on host cells. The genetic polymorphisms among different populations may influence the progression of COVID-19. However, the effects of IFNL4, ACE1, PKR, IFNG, and MBL2 in severe COVID-19 have not been systematically assessed. METHODS: We will include all relevant English and Chinese studies by searching the following electronic databases: PubMed, MEDLINE, Embase, Web of Science, Scopus, the Cochrane Library, and Google Scholar before March 31, 2022. Two researchers will independently screen and extract the literature. The methodological quality of the included studies will be evaluated by the Cochrane Handbook for Systematic Reviews of Interventions. RESULT: This systematic review and meta-analysis will summarize the association of IFNL4, ACE1, PKR, IFNG, MBL2 genetic polymorphisms, and severe COVID-19. The results will be submitted to a peer-reviewed journal once completed. CONCLUSION: The conclusion of our study will provide evidence for the early prevention of severe COVID-19. PROSPERO REGISTRATION NUMBER: CRD42022301735.


Subject(s)
COVID-19 , Mannose-Binding Lectin , COVID-19/genetics , Humans , Interferon-gamma , Interleukins , Mannose-Binding Lectin/genetics , Meta-Analysis as Topic , Polymorphism, Genetic , SARS-CoV-2 , Systematic Reviews as Topic
20.
PLoS One ; 17(3): e0265453, 2022.
Article in English | MEDLINE | ID: covidwho-1855002

ABSTRACT

Several SARS-CoV-2 variants emerged that harbor mutations in the surface unit of the viral spike (S) protein that enhance infectivity and transmissibility. Here, we analyzed whether ten naturally-occurring mutations found within the extended loop harboring the S1/S2 cleavage site of the S protein, a determinant of SARS-CoV-2 cell tropism and pathogenicity, impact S protein processing and function. None of the mutations increased but several decreased S protein cleavage at the S1/S2 site, including S686G and P681H, the latter of which is found in variants of concern B.1.1.7 (Alpha variant) and B.1.1.529 (Omicron variant). None of the mutations reduced ACE2 binding and cell-cell fusion although several modulated the efficiency of host cell entry. The effects of mutation S686G on viral entry were cell-type dependent and could be linked to the availability of cathepsin L for S protein activation. These results show that polymorphisms at the S1/S2 site can modulate S protein processing and host cell entry.


Subject(s)
Polymorphism, Genetic/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Animals , Chlorocebus aethiops , HEK293 Cells/virology , Humans , Immunoblotting , Vero Cells/virology
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