Background:
Immune responses following vaccination against COVID-19 with different vaccines and the waning of immunity vary within the population. Genetic host factors are likely to contribute to ...this variability. However, to the best of our knowledge, no study on G protein polymorphisms and vaccination responses against COVID-19 has been published so far.
Methods:
Antibodies against the SARS-CoV-2 spike protein and T-cell responses against a peptide pool of SARS-CoV-2 S1 proteins were measured 1 and 6 months after the second vaccination with mRNA-1273 in the main study group of 204 participants. Additionally, antibodies against the SARS-CoV-2 spike protein were measured in a group of 597 participants 1 month after the second vaccination with mRNA-1273. Genotypes of
GNB3
c.825C>T were determined in all participants.
Results:
The median antibody titer against the SARS-CoV-2 spike protein and median values of spots increment in the SARS-CoV-2 IFN-γ ELISpot assay against the S1-peptide pool were significantly decreased from months 1 to 6 (
p
< 0.0001). Genotypes of
GNB3
c.825C>T had no influence on the humoral immune response. At month 1, CC genotype carriers had significantly increased T-cell responses compared to CT (
p
= 0.005) or TT (
p
= 0.02) genotypes. CC genotype carriers had an almost 6-fold increased probability compared to TT genotype carriers and an almost 3-fold increased probability compared to T-allele carriers to mount a SARS-CoV-2-specific T-cell response above the median value.
Conclusion:
CC genotype carriers of the
GNB3
c.825C>T polymorphism have an increased T-cell immune response to SARS-CoV-2, which may indicate better T-cell-mediated protection against COVID-19 after vaccination with mRNA-1273.
Several factors, such as hypertension and diabetes mellitus, are known to influence the course of coronavirus disease 2019 (COVID-19). However, there is currently little information on genetic ...markers that influence the severity of COVID-19. In this study, we specifically investigated the single nucleotide polymorphism (SNP) rs4986790 in the
gene to identify a universal marker for preclinical prediction of COVID-19 disease progression.
We analyzed the influence of demographics, pre-existing conditions, inflammatory parameters at the time of hospitalization, and
rs4986790 genotype on the outcome of COVID-19 in a comprehensive cohort (N = 1570). We performed multivariable analysis to investigate the impact of each factor.
We confirmed that younger patient age and absence of pre-existing conditions were protective factors against disease progression. Furthermore, when comparing patients with mild SARS-CoV-2 infection with patients who required hospitalization or intensive care or even died due to COVID-19, the AG/GG genotype of
rs4986790 was found to be a protective factor against COVID-19 disease progression (OR: 0.51, 95% CI: 0.34 - 0.77,
= 0.001). In addition, we demonstrated that low levels of interleukin-6 (IL-6) and procalcitonin (PCT) had a favorable effect on COVID-19 disease severity. In the subsequent multivariable analysis, we confirmed the absence of cardiovascular disease, low levels of IL-6 and PCT, and
rs4986790 AG/GG genotypes as independent predictors of potential hospitalization and reduction of severe or fatal disease course.
In this study, we identified an additional genetic factor that may serve as an invariant predictor of COVID-19 outcome. The
rs4986790 AG/GG genotype reduced by half the risk of COVID-19 patients requiring hospitalization, intensive care or to have a fatal outcome. In addition, we were able to confirm the influence of previously known factors such as pre-existing conditions and inflammatory markers upon the onset of disease on the course of COVID-19. Based on these observations, we hereby provide another prognostic biomarker that could be used in routine diagnostics as a predictive factor for the severity of COVID-19 prior to SARS-CoV-2 infection.
Single-nucleotide polymorphisms in G protein subunits are linked to an increased risk of cardiovascular events among the general population. We assessed the effects of GNB3 c.825C > T, GNAQ ...−695/−694GC > TT, and GNAS c.393C > T polymorphisms on the risk of cardiovascular events among 454 patients undergoing renal replacement therapy. The patients were followed up for a median of 4.5 years after the initiation of dialysis. Carriers of the TT/TT genotype of GNAQ required stenting because of coronary artery stenosis (p = 0.0009) and developed cardiovascular events involving more than one organ system (p = 0.03) significantly earlier and more frequently than did the GC/TT or GC/GC genotypes. Multivariate analysis found that the TT/TT genotype of GNAQ was an independent risk factor for coronary artery stenosis requiring stent (hazard ratio, 4.5; p = 0.001), cardiovascular events (hazard ratio, 1.93; p = 0.04) and cardiovascular events affecting multiple organs (hazard ratio, 4.9; p = 0.03). In the subgroup of male patients left ventricular dilatation with abnormally increased LVEDD values occurred significantly more frequently in TT genotypes of GNB3 than in CT/CC genotypes (p = 0.007). Our findings suggest that male dialysis patients carrying the TT genotype of GNB3 are at higher risk of left ventricular dilatation and that dialysis patients carrying the TT/TT genotype of GNAQ are prone to coronary artery stenosis and severe cardiovascular events.
The transmembrane serine protease 2 (TMPRSS2) is the major host protease that enables entry of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) into host cells by spike (S) ...protein priming. Single nucleotide polymorphisms (SNPs) in the gene
have been associated with susceptibility to and severity of H1N1 or H1N9 influenza A virus infections. Functional variants may influence SARS-CoV-2 infection risk and severity of Coronavirus disease 2019 (COVID-19) as well. Therefore, we analyzed the role of SNPs in the gene
in a German case-control study. We performed genotyping of the SNPs rs2070788, rs383510, and rs12329760 in the gene
in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19. SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding their demographics. The CC genotype of
rs383510 was associated with a 1.73-fold increased SARS-CoV-2 infection risk, but was not correlated to severity of COVID-19. Neither
rs2070788 nor rs12329760 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. In a multivariable analysis (MVA), the rs383510 CC genotype remained an independent predictor for a 2-fold increased SARS-CoV-2 infection risk. In summary, our report appears to be the first showing that the intron variant rs383510 in the gene
is associated with an increased risk to SARS-CoV-2 infection in a German cohort.
Background
Despite the high level of protection against severe COVID-19 provided by the currently available vaccines some breakthrough infections occur. Until now, there is no information whether a ...potential risk of a breakthrough infection can be inferred from the level of antibodies after booster vaccination.
Methods
Levels of binding antibodies and neutralization capacity after the first, one and six month after the second, and one month after the third (booster) vaccination against COVID-19 were measured in serum samples from 1391 healthcare workers at the University Hospital Essen. Demographics, vaccination scheme, pre-infection antibody titers and neutralization capacity were compared between individuals with and without breakthrough infections.
Results
The risk of developing an Omicron breakthrough infection was independent of vaccination scheme, sex, body mass index, smoking status or pre-existing conditions. In participants with low pre-infection anti-spike antibodies (≤ 2641.0 BAU/ml) and weaker neutralization capacity (≤ 65.9%) against Omicron one month after the booster vaccination the risk for developing an Omicron infection was 10-fold increased (
P
= 0.001; 95% confidence interval, 2.36 - 47.55).
Conclusion
Routine testing of anti-SARS-CoV-2 IgG antibodies and surrogate virus neutralization can quantify vaccine-induced humoral immune response and may help to identify subjects who are at risk for a breakthrough infection. The establishment of thresholds for SARS-CoV-2 IgG antibody levels identifying “non”-, “low” and “high”-responders may be used as an indication for re-vaccination.
The c.825C>T single-nucleotide polymorphism (rs5443) of the guanine nucleotide-binding protein subunit β3 (GNB3) results in increased intracellular signal transduction via G-proteins. The present ...study investigated the effect of the GNB3 c.825C>T polymorphism on cardiovascular events among renal allograft recipients posttransplant. Our retrospective study involved 436 renal allograft recipients who were followed up for up to 8 years after transplant. The GNB3 c.825C>T polymorphism was detected with restriction fragment length polymorphism (RFLP) polymerase chain reaction (PCR). The GNB3 TT genotype was detected in 43 (10%) of 436 recipients. Death due to an acute cardiovascular event occurred more frequently among recipients with the TT genotype (4 9%) than among those with the CC/CT genotypes (7 2%; p = 0.003). The rates of myocardial infarction (MI)−free survival (p = 0.003) and acute peripheral artery occlusive disease (PAOD)−free survival (p = 0.004) were significantly lower among T-homozygous patients. A multivariate analysis showed that homozygous GNB3 c.825C>T polymorphism exerted only a mild effect for the occurrence of myocardial infarction (relative risk, 2.2; p = 0.065) or acute PAOD (relative risk, 2.4; p = 0.05) after renal transplant. Our results suggest that the homozygous GNB3 T allele exerts noticeable effects on the risk of MI and acute PAOD only in the presence of additional nonheritable risk factors.
SARS-CoV-2 infection is known to lead to severe morbidity and mortality in patients with liver cirrhosis. For this reason, vaccination of these patients against COVID-19 is widely recommended. ...However, data regarding immunogenicity in patients with liver cirrhosis is limited and even less is known about the kinetics of antibody response, as well as the optimal timing of booster immunization. We analyzed immunogenicity in 110 patients with liver cirrhosis after receiving two doses of the mRNA-based vaccine BNT162b2 following the standard protocol and compared these results to a control group consisting of 80 healthcare workers. One hundred and six patients with liver cirrhosis (96%) developed antibodies against SARS-CoV-2, compared to 79 (99%) in the control group (
= 0.400). Still, the median SARS-CoV-2 IgG titer was significantly lower in patients with liver cirrhosis compared to the control group (939 vs. 1905 BAU/mL,
= 0.0001). We also analyzed the strength of the antibody response in relation to the time between the second dose and antibody detection. Antibody titers remained relatively stable in the control group while showing a rapid and significant decrease in patients with liver cirrhosis. In conclusion, our data reveals a favorable initial outcome after vaccination with the COVID-19 vaccine BNT162b2 in cirrhotic patients but show a rapid deterioration of the antibody response after time, thereby giving a strong hint towards the importance of early booster immunization for this group of patients.
Early metastatic dissemination and evolution of disseminated cancer cells (DCCs) outside the primary tumor is one reason for the failure of adjuvant therapies because it generates molecular genotypes ...and phenotypes different from primary tumors, which still underlie therapy decisions. Since ERBB2 amplification in esophageal DCCs but not in primary tumor cells predict outcome, we aimed to establish an assay with diagnostic reliability for single DCCs or circulating tumor cells. For this, we evaluated copy number alterations of more than 600 single DCCs from multiple cancer types to define reference regions suitable for quantification of target regions, such as ERBB2. We then compared ERBB2 quantitative PCR (qPCR) measurements with fluorescent in situ hybridization (FISH) data of various breast cancer cell lines and identified the aberration‐calling threshold. The method was applied to two independent cohorts of esophageal cancer patients from Hamburg (n = 59) and Düsseldorf (n = 53). We found a high correlation between the single cell qPCR assay and the standard FISH assay (R = 0.98) and significant associations between amplification and survival for both patient cohorts (Hamburg (HH), p = 0.033; Düsseldorf (D), p = 0.052; pooled HH + D, p = 0.002) when applied to DCCs of esophageal cancer patients. Detection of a single ERBB2‐amplified DCC was the most important risk factor for death from esophageal cancer (relative risk = 4.22; 95% CI = 1.91–9.32; p < 0.001). In our study, we detected ERBB2‐amplified cells in 7% of patients. These patients could benefit from anti‐ERBB2 targeting therapies.
What's new?
About half of esophageal cancer patients are diagnosed with early disease and are eligible for surgical resection, increasing their chances of survival. To better predict prognosis in these patients, markers strongly indicative of early systemic cancer are needed. This report describes an assay for quantifying gene amplification of the tyrosine kinase ERBB2 in single disseminated cancer cells (DCCs), which are targets of adjuvant therapies. In DCCs of esophageal cancer patients in two separate cohorts, ERBB2 amplification was associated with survival. Moreover, ERBB2 gene amplification in DCCs was the most important factor for predicting death in uni‐ and multivariable analysis, suggesting that it is prognostically relevant in esophageal cancer and that targeting of ERBB2 in such high‐risk patients could improve their outcome.
Background and aims:
Albeit several factors which influence the outcome of corona virus disease (COVID-19) are already known, genetic markers which may predict the outcome of the disease in ...hospitalized patients are still very sparse. Thus, in this study, we aimed to analyze whether the single-nucleotide polymorphism (SNP) rs5443 in the gene
GNB3
, which was associated with higher T cell responses in previous studies, might be a suitable biomarker to predict T cell responses and the outcome of COVID-19 in a comprehensive German cohort.
Methods:
We analyzed the influence of demographics, pre-existing disorders, laboratory parameters at the time of hospitalization, and
GNB3
rs5443 genotype in a comprehensive cohort (N = 1570) on the outcome of COVID-19. In a sub cohort, we analyzed SARS-CoV-2-specific T cell responses and associated
GNB3
rs5443 genotypes. We investigated the influence of all factors on COVID-19 fatality in multivariable analysis.
Results:
We found a younger patient age, normotension or absence of diabetes mellitus or cardiovascular diseases, normal blood cell counts, and low inflammatory markers at hospital admission were protective factors against fatal course of disease. In addition, the rs5443 TT genotype was significantly associated with protection against COVID-19 fatality (OR: 0.60, 95% CI: 0.40–0.92,
p
= 0.02). We also observed significantly increased SARS-CoV-2-specific T cell responses in rs5443 TT genotype carriers (
p
= 0.01). Although we observed a significant association of the factors described previously in univariate analysis, only a younger age of the patients, normal blood cell counts, and the
GNB3
rs5443 TT genotype remained independent predictors against COVID-19 fatality in multivariable analysis.
Conclusion:
Immutable predictors for COVID-19 fatality are relatively rare. In this study we could show that the TT genotype of the SNP rs5443 in the gene
GNB3
is associated with protection against COVID-19 fatality. It was as well correlated to higher SARS-CoV-2-specific T cell responses, which could result in a milder course of disease in those patients. Based on those observations we hereby provide a further prognostic biomarker, which might be used in routine diagnostics as a predictive factor for COVID-19 mortality already upon hospitalization.
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