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1.
Glycoconj J ; 39(2): 207-218, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1800338

ABSTRACT

In 1990, 90 years after the discovery of ABO blood groups by Karl Landsteiner, my research team at the Molecular Biology Laboratory of the now-defunct Biomembrane Institute elucidated the molecular genetic basis of the ABO polymorphism. Henrik Clausen, Head of the Immunology Laboratory, initiated the project by isolating human group A transferase (AT), whose partial amino acid sequence was key to its success. Sen-itiroh Hakomori, the Scientific Director, provided all the institutional support. The characterization started from the 3 major alleles (A1, B, and O), and proceeded to the alleles of A2, A3, Ax and B3 subgroups and also to the cis-AB and B(A) alleles, which specify the expression of A and B antigens by single alleles. In addition to the identification of allele-specific single nucleotide polymorphism (SNP) variations, we also experimentally demonstrated their functional significance in glycosyltransferase activity and sugar specificity of the encoded proteins. Other scientists interested in blood group genes later characterized more than 250 ABO alleles. However, recent developments in next-generation sequencing have enabled the sequencing of millions of human genomes, transitioning from the era of genetics to the era of genomics. As a result, numerous SNP variations have been identified in the coding and noncoding regions of the ABO gene, making ABO one of the most studied loci for human polymorphism. As a tribute to Dr. Hakomori's scientific legacy, a historical overview in molecular genetic/genomic studies of the human ABO gene polymorphism is presented, with an emphasis on early discoveries made at his institute.


Subject(s)
ABO Blood-Group System , Polymorphism, Genetic , ABO Blood-Group System/genetics , Alleles , Genomics , Humans , Molecular Biology , Phenotype
2.
Sci Rep ; 12(1): 3854, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1799575

ABSTRACT

The outbreak of COVID-19 caused by infection with SARS-CoV-2 virus has become a worldwide pandemic, and the number of patients presenting with respiratory failure is rapidly increasing in Japan. An international meta-analysis has been conducted to identify genetic factors associated with the onset and severity of COVID-19, but these factors have yet to be fully clarified. Here, we carried out genomic analysis based on a genome-wide association study (GWAS) in Japanese COVID-19 patients to determine whether genetic factors reported to be associated with the onset or severity of COVID-19 in the international meta-GWAS are replicated in the Japanese population, and whether new genetic factors exist. Although no significant genome-wide association was detected in the Japanese GWAS, an integrated analysis with the international meta-GWAS identified for the first time the involvement of the IL17A/IL17F gene in the severity of COVID-19. Among nine genes reported in the international meta-GWAS as genes involved in the onset of COVID-19, the association of FOXP4-AS1, ABO, and IFNAR2 genes was replicated in the Japanese population. Moreover, combined analysis of ABO and FUT2 genotypes revealed that the presence of oral AB antigens was significantly associated with the onset of COVID-19. FOXP4-AS1 and IFNAR2 were also significantly associated in the integrated analysis of the Japanese GWAS and international meta-GWAS when compared with severe COVID-19 cases and the general population. This made it clear that these two genes were also involved in not only the onset but also the severity of COVID-19. In particular, FOXP4-AS1 was not found to be associated with the severity of COVID-19 in the international meta-GWAS, but an integrated analysis with the Japanese GWAS revealed an association with severity. Individuals with the SNP risk allele found between IL17A and IL17F had significantly lower mRNA expression levels of IL17F, suggesting that activation of the innate immune response by IL17F may play an important role in the severity of SARS-CoV-2 infection.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/pathology , Interleukin-17/genetics , Saliva/metabolism , Adult , Aged , Aged, 80 and over , Alleles , COVID-19/genetics , Female , Genome-Wide Association Study , Humans , Japan , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index , Young Adult
4.
Gene ; 820: 146235, 2022 Apr 30.
Article in English | MEDLINE | ID: covidwho-1778131

ABSTRACT

The relationship of single nucleotide polymorphisms (SNPs) in patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 with outcomes in patients with hepatitis C infection (HCV) is unclear. This study aimed to evaluate the association of PNPLA3, TM6SF2, and MBOAT7 with the baseline fibrosis stage and progression of liver fibrosis after HCV eradication with direct antiviral agents (DAAs). A total of 171 patients who received the DAAs at the Peking University First Hospital between June 2015 and June 2020 were included in the retrospective cohort. Transient elastography was used to determine liver stiffness measurements (LSMs) at the baseline, the end of treatment (EOT), 24 weeks after treatment (W24), and the last follow-up (LFU) visit. We used the QIAamp Blood Mini Kit (Qiagen) for whole blood genomic DNA extraction and polymerase chain reaction for PNPLA3, TM6SF2, and MBOAT7 amplification of the target gene. The PNPLA3 rs738409 SNP was associated with the baseline fibrosis stage in multivariate logistic regression analysis adjusted for other factors, and the adjusted odds ratio (OR) for advanced fibrosis (≥F3) at baseline was 2.52 (95% confidence interval[CI] = 1.096-5.794, p = 0.03). The G and GG alleles were predictive of advanced fibrosis (OR = 1.98, 95% CI = 1.021-4.196, p = 0.015; OR = 3.12, 95% CI = 1.572-6.536, p = 0.005). Similarly, the OR of TM6SF2 rs58542926 at baseline was 2.608 (95% CI = 1.081-6.29, p = 0.033). T and TT alleles were predictive of advanced fibrosis (OR = 2.3, 95% CI = 1.005-5.98, p = 0.007; OR = 3.05, 95% CI = 1.32-6.87, p = 0.001). After adjustment, the MBOAT7 rs641738 T plus TT alleles were not independently associated with the baseline fibrosis stage (95% CI = 0.707-2.959, p = 0.312). At the EOT, there were 35 patients and 136 patients in the fibrosis improvement and fibrosis non-improvement group, respectively. Logistic regression analysis showed that the G allele in PNPLA3 rs738409 was associated with fibrosis progression (OR = 2.47, 95% CI = 1.125-5.89, p = 0.003). The GG alleles were predictive of fibrosis progression (OR = 2.95, 95% CI = 1.35-6.35, p = 0.005). Similarly, the ORs of the T and TT alleles in TM6SF2 rs58542926 for fibrosis progression were 1.82 and 2.21, respectively (95% CI = 1.006-5.373, p = 0.045; 95% CI = 1.18-5.75, p = 0.01). At the W24 visit, we found that there was an association between the G allele in PNPLA3 rs738409 and fibrosis progression (OR = 2.218, 95% CI = 1.095-5.631, p = 0.015). Moreover, GG alleles were also predictive for fibrosis progression (OR = 2.558, 95% CI = 1.252-5.15, p = 0.008). Similarly, the OR of T allele and TT alleles in TM6SF2 rs58542926 for fibrosis progression was 2.056 and 2.652 (95% CI = 1.013-5.592, p = 0.038; 95% CI = 1.25-5.956, p = 0.015). For additional affirmation, we surveyed fibrosis progression utilizing the Cox proportional hazards model. G and GG alleles in PNPLA3 rs738409 were associated with an increased risk of progression to advanced fibrosis in multivariate model (hazard ratio [HR]1.566, 95% CI = 1.02-2.575, p = 0.017; and HR2.109, 95% CI = 1.36-3.271, p = 0.001, respectively). Besides, T and TT alleles in TM6SF2 rs58542926 were associated with an increased risk of progression to advanced fibrosis in multivariate model (HR = 1.322, 95% CI = 1.003-1.857, p = 0.045; and HR = 1.855, 95% CI = 1.35-2.765, p = 0.006, respectively). In contrast, rs641738 in MBOAT7 did not show a significant trend in the univariate and multivariate models. The PNPLA3 CG/GG SNP at rs738409 and TM6SF2 CT/TT SNP at rs58542926 were associated with the baseline fibrosis stage and fibrosis progression after HCV eradication with DAAs.


Subject(s)
Acyltransferases/economics , Acyltransferases/genetics , Liver Cirrhosis/genetics , Membrane Proteins/economics , Membrane Proteins/genetics , Phospholipases A2, Calcium-Independent/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Alleles , Disease Progression , Female , Genetic Predisposition to Disease , Hepacivirus , Hepatitis C/complications , Hepatitis C/virology , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/genetics , Prognosis , Retrospective Studies
5.
Clin Immunol ; 236: 108954, 2022 03.
Article in English | MEDLINE | ID: covidwho-1734267

ABSTRACT

Polymorphisms of Fcγ receptors have been associated with variable responses to infections. We determined the association of functional polymorphisms rs1801274 in the FCGR2A and rs396991 in the FCGR3A with COVID-19 severity. This study involved 453 patients with severe COVID-19, in which the FCGR2A rs1801274 G-allele (131-Arg) was significantly associated with death (p = 0.02, OR = 1.47). This effect was independent of age and increased IL6 and D-Dimer levels. This study suggests that the FCGR2A gene might be associated with the risk of death among COVID-19 patients. Our study has several limitations, mainly the limited number of patients and the inclusion of a single population. It is thus necessary to confirm this result in larger cohorts from different populations.


Subject(s)
COVID-19 , Receptors, IgG , Alleles , COVID-19/genetics , Genetic Predisposition to Disease , Genotype , Humans , Polymorphism, Single Nucleotide , Receptors, IgG/genetics
6.
Front Immunol ; 13: 812940, 2022.
Article in English | MEDLINE | ID: covidwho-1731774

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, affecting more than 219 countries and causing the death of more than 5 million people worldwide. The genetic background represents a factor that predisposes the way the host responds to SARS-CoV-2 infection. In this sense, genetic variants of ACE and ACE2 could explain the observed interindividual variability to COVID-19 outcomes. In order to improve the understanding of how genetic variants of ACE and ACE2 are involved in the severity of COVID-19, we included a total of 481 individuals who showed clinical manifestations of COVID-19 and were diagnosed by reverse transcription PCR (RT-PCR). Genomic DNA was extracted from peripheral blood and saliva samples. ACE insertion/deletion polymorphism was evaluated by the high-resolution melting method; ACE single-nucleotide polymorphism (SNP) (rs4344) and ACE2 SNPs (rs2285666 and rs2074192) were genotyped using TaqMan probes. We assessed the association of ACE and ACE2 polymorphisms with disease severity using logistic regression analysis adjusted by age, sex, hypertension, type 2 diabetes, and obesity. The severity of the illness in our study population was divided as 31% mild, 26% severe, and 43% critical illness; additionally, 18% of individuals died, of whom 54% were male. Our results showed in the codominant model a contribution of ACE2 gene rs2285666 T/T genotype to critical outcome [odds ratio (OR) = 1.83; 95%CI = 1.01-3.29; p = 0.04] and to require oxygen supplementation (OR = 1.76; 95%CI = 1.01-3.04; p = 0.04), in addition to a strong association of the T allele of this variant to develop critical illness in male individuals (OR = 1.81; 95%CI = 1.10-2.98; p = 0.02). We suggest that the T allele of rs2285666 represents a risk factor for severe and critical outcomes of COVID-19, especially for men, regardless of age, hypertension, obesity, and type 2 diabetes.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Peptidyl-Dipeptidase A/genetics , Polymorphism, Single Nucleotide/genetics , Alleles , COVID-19/virology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/virology , Genotype , Humans , Male , SARS-CoV-2/pathogenicity
7.
J Med Virol ; 94(4): 1502-1512, 2022 04.
Article in English | MEDLINE | ID: covidwho-1718395

ABSTRACT

The present coronavirus disease 2019 (COVID-19) is spreading rapidly and existing data has suggested a number of susceptibility factors for developing a severe course of the disease.  The current case-control experiment is aimed to study the associations of genetic polymorphisms in tumor necrosis factors (TNFs) with COVID-19 and its mortality rate. A total of 550 participants (275 subjects and 275 controls) were enrolled. The tetra-amplification refractory mutation system polymerase chain reaction technique was recruited to detect -308G>A TNFα and +252A>G TNFß polymorphisms among the Iranian subjects. We demonstrated that carriers of the G allele of TNFß-252A/G, rs909253 A>G were more frequent in COVID-19 subjects compared to the healthy group and this allele statistically increased the disease risk (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.23-1.96, p < 0.0001). At the same time, the A allele of TNFα-311A/G, rs1800629 G>A moderately decreased the risk of COVID-19 (OR = 0.68, 95% CI = 0.53-0.86, p < 0.002). Also, we analyzed the various genotypes regarding the para-clinical and disorder severity; we found that in the AA genotype of TNFß-252A/G (rs909253 A>G), the computed tomography scan pattern was different in comparison to cases carrying the AG genotype with p1 < 0.001. In addition, in the severe cases of COVID-19, leukocyte and neutrophil count and duration of intensive care unit hospitalization in the deceased patients were significantly increased (p < 0.001). Moreover, the TNFα-311A/G (rs1800629 G>A) variant is likely to change the pattern of splicing factor sites. Our findings provided deep insights into the relationship between TNFα/TNFß polymorphisms and severe acute respiratory syndrome coronavirus 2. Replicated studies may give scientific evidence for exploring molecular mechanisms of COVID-19 in other ethnicities.


Subject(s)
COVID-19/genetics , COVID-19/mortality , Lymphotoxin-alpha/genetics , Tumor Necrosis Factor-alpha/genetics , Adult , Aged , Alleles , Case-Control Studies , Computer Simulation , Female , Genetic Predisposition to Disease/genetics , Humans , Iran/epidemiology , Logistic Models , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics
9.
PLoS One ; 17(2): e0264009, 2022.
Article in English | MEDLINE | ID: covidwho-1703850

ABSTRACT

BACKGROUND: Populations seem to respond differently to the global pandemic of severe acute respiratory syndrome coronavirus 2. Recent studies show individual variability in both susceptibility and clinical response to COVID-19 infection. People with chronic obstructive pulmonary disease (COPD) constitute one of COVID-19 risk groups, being already associated with a poor prognosis upon infection. This study aims contributing to unveil the underlying reasons for such prognosis in people with COPD and the variability in the response observed across worldwide populations, by looking at the genetic background as a possible answer to COVID-19 infection response heterogeneity. METHODS: SNPs already associated with susceptibility to COVID-19 infection (rs286914 and rs12329760) and severe COVID-19 with respiratory failure (rs657152 and rs11385942) were assessed and their allelic frequencies used to calculate the probability of having multiple risk alleles. This was performed on a Portuguese case-control COPD cohort, previously clinically characterized and genotyped from saliva samples, and also on worldwide populations (European, Spanish, Italian, African, American and Asian), using publicly available frequencies data. A polygenic risk analysis was also conducted on the Portuguese COPD cohort for the two mentioned phenotypes, and also for hospitalization and survival to COVID-19 infection. FINDINGS: No differences in genetic risk for COVID-19 susceptibility, hospitalization, severity or survival were found between people with COPD and the control group (all p-values > 0.01), either considering risk alleles individually, allelic combinations or polygenic risk scores. All populations, even those with European ancestry (Portuguese, Spanish and Italian), showed significant differences from the European population in genetic risk for both COVID-19 susceptibility and severity (all p-values < 0.0001). CONCLUSION: Our results indicate a low genetic contribution for COVID-19 infection predisposition or worse outcomes observed in people with COPD. Also, our study unveiled a high genetic heterogeneity across major world populations for the same alleles, even within European sub-populations, demonstrating the need to build a higher resolution European genetic map, so that differences in the distribution of relevant alleles can be easily accessed and used to better manage diseases, ultimately, safeguarding populations with higher genetic predisposition to such diseases.


Subject(s)
COVID-19/genetics , Pulmonary Disease, Chronic Obstructive/diagnosis , Aged , Alleles , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Phenotype , Polymorphism, Single Nucleotide , Portugal , Pulmonary Disease, Chronic Obstructive/complications , Respiratory Insufficiency/etiology , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index , Survival Analysis , /genetics
10.
J Virol Methods ; 303: 114497, 2022 05.
Article in English | MEDLINE | ID: covidwho-1693166

ABSTRACT

Tracking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants through whole genome sequencing (WGS) is vital for effective infection control and prevention (IPC) measures, but can be time-consuming and resource-heavy. We describe an in-house validation of an allele-specific polymerase chain reaction (ASP) variant assay to detect variants of concern (VOC). ASP sensitivity for detecting Delta, Alpha and Beta was 99.45 %, 100 %, and 66.67 %, respectively, compared with WGS. Specificity was 100 % in detecting all three VOC. ASP generated results 1.3 days faster compared with WGS. These findings suggest using variant assays such as ASP may enhance epidemiological surveillance and IPC measures.


Subject(s)
COVID-19 , SARS-CoV-2 , Alleles , COVID-19/diagnosis , Humans , Mutation , Polymerase Chain Reaction , SARS-CoV-2/genetics
11.
Microbiol Spectr ; 10(1): e0068121, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1691411

ABSTRACT

The N501Y amino acid mutation caused by a single point substitution A23063T in the spike gene of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is possessed by three variants of concern (VOCs), B.1.1.7, B.1.351, and P.1. A rapid screening tool using this mutation is important for surveillance during the coronavirus disease 2019 (COVID-19) pandemic. We developed and validated a single nucleotide polymorphism real-time reverse transcription PCR assay using allelic discrimination of the spike gene N501Y mutation to screen for potential variants of concern and differentiate them from SARS-CoV-2 lineages without the N501Y mutation. A total of 160 clinical specimens positive for SARS-CoV-2 were characterized as mutant (N501Y) or N501 wild type by Sanger sequencing and were subsequently tested with the N501Y single nucleotide polymorphism real-time reverse transcriptase PCR assay. Our assay, compared to Sanger sequencing for single nucleotide polymorphism detection, demonstrated positive percent agreement of 100% for all 57 specimens displaying the N501Y mutation, which were confirmed by Sanger sequencing to be typed as A23063T, including one specimen with mixed signal for wild type and mutant. Negative percent agreement was 100% in all 103 specimens typed as N501 wild type, with A23063 identified as wild type by Sanger sequencing. The identification of circulating SARS-CoV-2 lineages carrying an N501Y mutation is critical for surveillance purposes. Current identification methods rely primarily on Sanger sequencing or whole-genome sequencing, which are time consuming, labor intensive, and costly. The assay described herein is an efficient tool for high-volume specimen screening for SARS-CoV-2 VOCs and for selecting specimens for confirmatory Sanger or whole-genome sequencing. IMPORTANCE During the coronavirus disease 2019 (COVID-19) pandemic, several variants of concern (VOCs) have been detected, for example, B.1.1.7, B.1.351, P.1, and B.1.617.2. The VOCs pose a threat to public health efforts to control the spread of the virus. As such, surveillance and monitoring of these VOCs is of the utmost importance. Our real-time RT-PCR assay helps with surveillance by providing an easy method to quickly survey SARS-CoV-2 specimens for VOCs carrying the N501Y single nucleotide polymorphism (SNP). Samples that test positive for the N501Y mutation in the spike gene with our assay can be sequenced to identify the lineage. Thus, our assay helps to focus surveillance efforts and decrease turnaround times.


Subject(s)
COVID-19/diagnosis , Mutation, Missense , Point Mutation , Real-Time Polymerase Chain Reaction/methods , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Alleles , Amino Acid Substitution , COVID-19/epidemiology , COVID-19/virology , Genes, Viral , Humans , Mass Screening , Ontario/epidemiology , Polymorphism, Single Nucleotide , Population Surveillance , Prevalence , Reproducibility of Results , Sensitivity and Specificity
12.
Cytokine ; 143: 155525, 2021 07.
Article in English | MEDLINE | ID: covidwho-1628419

ABSTRACT

Interferon gamma (IFN-γ) is a crucial cytokine in host immune response to hepatitis B virus (HBV) infection. This study aimed to determine whether a functional polymorphism +874T/A in IFN-γ gene linked to high and low producer phenotypes [IFN-γ (+874Thigh â†’ Alow)] may alter the outcomes of chronic HBV infection in Tunisian population. The +874T/A was analysed by ARMS-PCR method in the group of 200 patients chronically infected with HBV and 200 healthy controls. We observed that minor +874A allele, minor +874AA and +874TA genotypes were significantly more frequent in the chronic hepatitis B group in comparison to the control group [49 vs. 31%, P < 10-4; 24 vs. 13%, P < 10-4; 52 vs. 38%, P < 10-4; respectively]. Besides, they were associated with susceptibility to hepatitis B infection [OR = 2.15, 3.87 and 2.84, respectively]. The minor +874A allele and +874AA genotype were statistically more representative in the sub-group of patients with high viral DNA load when compared with the sub-group of patients with low HBV DNA load [(57% vs. 43%, P = 0.003, OR = 1.79); (33% vs. 14%, P = 0.003, OR = 3.59), respectively]. Collectively, our study suggests an association between the IFN-γ +874T/A SNP and persistence of HBV by the enhancement of HBV DNA replication.


Subject(s)
DNA Replication , Genetic Association Studies , Genetic Predisposition to Disease , Hepatitis B virus/physiology , Hepatitis B, Chronic/genetics , Interferon-gamma/genetics , Polymorphism, Single Nucleotide/genetics , Virus Replication/physiology , Adult , Alleles , Case-Control Studies , DNA, Viral/genetics , Female , Gene Frequency/genetics , Hepatitis B, Chronic/virology , Humans , Male , Viral Load/genetics
14.
Front Immunol ; 12: 774491, 2021.
Article in English | MEDLINE | ID: covidwho-1648672

ABSTRACT

Common human coronaviruses have been circulating undiagnosed worldwide. These common human coronaviruses share partial sequence homology with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); therefore, T cells specific to human coronaviruses are also cross-reactive with SARS-CoV-2 antigens. Herein, we defined CD4+ T cell responses that were cross-reactive with SARS-CoV-2 antigens in blood collected in 2016-2018 from healthy donors at the single allele level using artificial antigen-presenting cells (aAPC) expressing a single HLA class II allotype. We assessed the allotype-restricted responses in the 42 individuals using the aAPCs matched 22 HLA-DR alleles, 19 HLA-DQ alleles, and 13 HLA-DP alleles. The response restricted by the HLA-DR locus showed the highest magnitude, and that by HLA-DP locus was higher than that by HLA-DQ locus. Since two alleles of HLA-DR, -DQ, and -DP loci are expressed co-dominantly in an individual, six different HLA class II allotypes can be used to the cross-reactive T cell response. Of the 16 individuals who showed a dominant T cell response, five, one, and ten showed a dominant response by a single allotype of HLA-DR, -DQ, and -DP, respectively. The single allotype-restricted T cells responded to only one antigen in the five individuals and all the spike, membrane, and nucleocapsid proteins in the six individuals. In individuals heterozygous for the HLA-DPA and HLA-DPB loci, four combinations of HLA-DP can be expressed, but only one combination showed a dominant response. These findings demonstrate that cross-reactive T cells to SARS-CoV-2 respond with single-allotype dominance.


Subject(s)
Alleles , Antigens, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Genes, MHC Class II , HLA-D Antigens/genetics , SARS-CoV-2/immunology , Adult , Antigen-Presenting Cells/immunology , Blood Donors , COVID-19/virology , Cells, Cultured , Cross Reactions , Enzyme-Linked Immunospot Assay/methods , Female , HLA-D Antigens/immunology , Healthy Volunteers , Humans , Immunoglobulin Allotypes/immunology , Male , Young Adult
15.
Infect Genet Evol ; 98: 105227, 2022 03.
Article in English | MEDLINE | ID: covidwho-1648267

ABSTRACT

INTRODUCTION: The severity of SARS-CoV-2 induced coronavirus disease 19 (COVID-19) depends on the presence of risk factors and the hosts' gene variability. There are preliminary results that gene polymorphisms of the renin-angiotensin system can influence the susceptibility to and mortality from COVID-19. Angiotensin II type 1 receptor (AT1R) might be a gene candidate that exerts such influence. The aim of this study was to elaborate on the association between A1166C at1r polymorphic variants and the susceptibility to and severity of COVID-19 in the Ukrainian population. METHODS: The study population consisted of the Ukrainian population (Poltava region) with COVID-19, divided into three clinical groups in accordance with oxygen requirement: patients without oxygen therapy (n = 110), with non-invasive (n = 136) and invasive (n = 36) oxygen therapy. The A1166C polymorphism of the at1r was determined by polymerase chain reaction with subsequent restrictase analysis. In an attempt to better explain the role of the A1166C at1r polymorphism we compared its association with COVID-19, essential hypertension (n = 79), renoparenchimal hypertension (n = 30) and dyscirculatory encephalopathy (n = 112). The data for this comparison were obtained by meta-analysis. RESULTS: We observed significant differences in the frequency of AA, AC and CC genotypes in the groups of COVID-19 patients with non-invasive and invasive oxygen therapy in comparison with control subjects as well as in the frequency of combined AC + CC genotype between the groups of COVID-19 patients with any types of oxygen therapy and patients without oxygen therapy. The frequency of the 1166C allele was higher in COVID-19 patients with invasive oxygen therapy (OR = 2.06; CI (1.20-3.53); p = 0.013). We obtained important results indicating that there were no differences between the frequency of at1r polymorphisms in patients with cardiovascular disease and severe COVID-19 with invasive oxygen therapy as well as those who died due to COVID-19. CONCLUSION: Our study indicated the presence of an association between the A1166C at1r polymorphisms and the severity of COVID-19 in the Ukrainian population. It seems that in carriers of 1166C at1r, the severity of COVID-19 and oxygen dependency is higher as compared to the A allele carriers, possibly, due to cardiovascular disorders.


Subject(s)
COVID-19/genetics , COVID-19/therapy , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Receptor, Angiotensin, Type 1/genetics , SARS-CoV-2/genetics , Severity of Illness Index , Adult , Alleles , COVID-19/epidemiology , Female , Genotype , Humans , Male , Middle Aged , Respiration, Artificial/methods , Respiration, Artificial/statistics & numerical data , Risk Factors , Ukraine/epidemiology
16.
HLA ; 99(4): 281-312, 2022 04.
Article in English | MEDLINE | ID: covidwho-1642778

ABSTRACT

HLA is crucial for appropriate immune responses in several viral infections, as well as in severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The unpredictable nature of Coronavirus Disease 19 (COVID-19), observed in both inter-individual and inter-population level, raises the question, to what extent the HLA, as part of host genetic factors, contribute to disease susceptibility and prognosis. We aimed to identify significant HLAs, those were investigated till now, for their association with COVID-19. Three databases were searched (PubMed, Cochrane library, and Web of Science) and articles published between January 2020 and May 2021 were included for in-depth analysis. Two separate teams including four observers independently extracted the summary data, with discrepancies resolved by consensus. This study is registered with PROSPERO (CRD42021251670). Of 1278 studies identified, 36 articles were included consisting of 794,571 participants. Countries from the European region appeared in the highest number of studies and vice versa for countries from South East Asia. Among 117 significantly altered alleles, 85 (72.65%) were found to have a positive correlation with COVID-19 and 33 (27.35%) alleles were observed having a negative correlation. HLA A*02 is the most investigated allele (n = 18) and showed contradictory results. Non-classical HLA E was explored by only one study and it showed that E*01:01 is associated with severity. Both in silico and wet lab data were considered and contrasting results were found from two approaches. Although several HLAs depicted significant association, nothing conclusive could be drawn because of heterogeneity in study designs, HLA typing methods, and so forth. This systematic review shows that, though HLAs play role in COVID-19 susceptibility, severity, and mortality, more uniformly designed, interrelated studies with the inclusion of global data, for use in evidence-based medicine are needed.


Subject(s)
COVID-19 , Alleles , COVID-19/genetics , HLA Antigens/genetics , Humans , Polymorphism, Genetic , SARS-CoV-2
17.
Clin Immunol ; 235: 108929, 2022 02.
Article in English | MEDLINE | ID: covidwho-1629722

ABSTRACT

Toll-like receptor 3 (TLR3) and TLR7 genes are involved in the host immune response against viral infections including SARS-COV-2. This study aimed to investigate the association between the TLR3(rs3775290) and TLR7(rs179008) polymorphisms with the prognosis and susceptibility to COVID-19 pneumonia accompanying SARS-COV-2 infection. This case-control study included 236 individuals: 136 COVID-19 pneumonia patients and 100 age and sex-matched controls. Two polymorphisms (TLR3 rs3775290 and TLR7 rs179008) were genotyped by allelic discrimination through TaqMan real-time PCR. This study also investigated predictors of mortality in COVID-19 pneumonia through logistic regression. The mutant 'T/T' genotypes and the 'T' alleles of TLR3(rs3775290) and TLR7(rs179008) polymorphisms were significantly associated with increased risk of COVID-19 pneumonia. This study did not report association between the mutant 'T/T' genotypes of TLR3(rs3775290) and TLR7(rs179008) and the disease outcome. In multivariate analysis, the independent predictors of mortality in COVID-19 pneumonia were male sex, SPO2 ≤ 82%, INR > 1, LDH ≥ 1000 U/l, and lymphocyte count<900/mm3 (P < 0.05).


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease/genetics , Pneumonia/genetics , Polymorphism, Single Nucleotide , Toll-Like Receptor 3/genetics , Toll-Like Receptor 7/genetics , Aged , Alleles , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Pneumonia/diagnosis , Pneumonia/virology , Prognosis , ROC Curve , Risk Factors , SARS-CoV-2/physiology
18.
HLA ; 99(3): 183-191, 2022 03.
Article in English | MEDLINE | ID: covidwho-1621962

ABSTRACT

The polymorphism of the HLA system has been extensively studied in COVID-19 infection, however there are no data about the role of HLA on vaccine response. We report here the HLA-A, -B, -C, and DRB1 allelic frequencies of n = 111 individuals after BNT162b2 mRNA vaccine, selected on the basis of lower antibody levels (<5% percentile) after the second dose among a total of n = 2569 vaccinees, and compare them with the frequencies of a reference population. We found that differences in the frequencies of the alleles HLA-A*03:01, A*33:03, B*58:01 and at least one haplotype (HLA-A*24:02~C*07:01~B*18:01~DRB1*11:04) are associated with a weaker antibody response after vaccination, together with the age of vaccinees. Our results might suggest a role played by some HLA alleles or haplotypes in antibody production after the BNT162b2 mRNA vaccine, giving insights into the tracking of potentially susceptible individuals across populations. Further studies are needed to better define our exploratory findings and dissect the role of HLA polymorphism on response to anti-COVID-19 vaccines.


Subject(s)
Antibody Formation , COVID-19 , HLA-DRB1 Chains , Alleles , Antibodies, Viral/immunology , COVID-19/prevention & control , Gene Frequency , HLA-DRB1 Chains/genetics , Haplotypes , Humans , SARS-CoV-2 , Vaccines, Synthetic/immunology
19.
Rev Med Virol ; 31(6): e2236, 2021 11.
Article in English | MEDLINE | ID: covidwho-1573896

ABSTRACT

Modifications in HLA-I expression are found in many viral diseases. They represent one of the immune evasion strategies most widely used by viruses to block antigen presentation and NK cell response, and SARS-CoV-2 is no exception. These alterations result from a combination of virus-specific factors, genetically encoded mechanisms, and the status of host defences and range from loss or upregulation of HLA-I molecules to selective increases of HLA-I alleles. In this review, I will first analyse characteristic features of altered HLA-I expression found in SARS-CoV-2. I will then discuss the potential factors underlying these defects, focussing on HLA-E and class-I-related (like) molecules and their receptors, the most documented HLA-I alterations. I will also draw attention to potential differences between cells transfected to express viral proteins and those presented as part of authentic infection. Consideration of these factors and others affecting HLA-I expression may provide us with improved possibilities for research into cellular immunity against viral variants.


Subject(s)
Antigenic Variation , COVID-19/immunology , Clonal Anergy , Histocompatibility Antigens Class I/immunology , Immune Evasion , SARS-CoV-2/genetics , Alleles , COVID-19/pathology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Cytotoxicity, Immunologic , Gene Expression , Histocompatibility Antigens Class I/genetics , Humans , Immunity, Cellular , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , NK Cell Lectin-Like Receptor Subfamily C/genetics , NK Cell Lectin-Like Receptor Subfamily C/immunology , NK Cell Lectin-Like Receptor Subfamily D/genetics , NK Cell Lectin-Like Receptor Subfamily D/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology
20.
PLoS One ; 16(11): e0260298, 2021.
Article in English | MEDLINE | ID: covidwho-1554516

ABSTRACT

BACKGROUND: Some studies revealed that despite having sufficient sun exposure and dietary supply, the level of serum 25(OH)D in Bangladeshi adults is lower than its normal range. Genetic pattern of an individual is also an essential factor that regulates the level of serum 25(OH)D. However, the genetic variations of CYP2R1 (rs10741657) and their association with low serum 25(OH)D level in Bangladeshi adults are yet to be explored. OBJECTIVE: This study was conducted to determine the frequency of variants of rs10741657 of CYP2R1 gene and its association with low serum 25(OH)D level among Bangladeshi adults. METHOD: This pilot study was conducted among thirty individuals with low serum 25(OH)D level as the study population and ten subjects with sufficient serum 25(OH)D level as controls based on the inclusion and exclusion criteria. Genetic analysis of rs10741657 of CYP2R1 including primer designing, DNA extraction, PCR of target region with purification and Sanger sequencing of the PCR products were done accordingly. For statistical analysis, One-way ANOVA followed by LSD test, Freeman-Halton extension of Fisher's exact test, Chi-square test (χ2) test and unpaired student t-test were performed. RESULTS: In this study, genetic variants of CYP2R1 (rs10741657) among the study population were genotype GG (63.30%), GA (30%) and AA (6.7%). Minor allele frequency of the study population was 0.217. The association between GG and GA genotypes of CYP2R1 (rs10741657) with low serum 25(OH)D level among the study population was found and it was statistically significant. Statistically significant differences were also observed between the genotypes and alleles of the study population and controls. CONCLUSIONS: The presence of 'GG' and 'GA' genotypes of rs1041657 in CYP2R1 gene is associated with low serum 25(OH)D level among Bangladeshi adults in this pilot study.


Subject(s)
/genetics , Cholestanetriol 26-Monooxygenase/genetics , Cytochrome P450 Family 2/genetics , Genetic Variation/genetics , Vitamin D/analogs & derivatives , Adult , Alleles , Chi-Square Distribution , Female , Gene Frequency/genetics , Genetic Testing/methods , Genotype , Humans , Male , Pilot Projects , Polymerase Chain Reaction/methods , Vitamin D/blood
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