Influence of HLA-G 3' Untranslated Region Haplotypes and SNP +3422 Gene Variants as Host Genetic Factors on the Outcomes of SARS-CoV-2 Infection During Acute and Post-Acute Phases in a German Cohort.

HLA-G, an important immune-checkpoint (IC) molecule that exerts inhibitory signalling on immune effector cells, has been suggested to represent a key player in regulating the immune response to Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2). Since specific single-nucleotide polymorphisms (SNP) in the HLA-G 3'untranslated region (UTR), which arrange as haplotypes, are crucial for the regulation of HLA-G expression, we analysed the contribution of these genetic variants as host factors in SARS-CoV-2 infection during acute and post-acute phases. HLA-G gene polymorphisms in the 3'UTR were investigated by sequencing in an unvaccinated Coronavirus Disease 2019 (COVID-19) cohort during acute SARS-CoV-2 infection (N = 505) and in the post-acute phase (N = 253).

Early CYP3A5 Genotype-Based Adjustment of Tacrolimus Dosage Reduces Risk of De Novo Donor-Specific HLA Antibodies and Rejection among CYP3A5-Expressing Renal Transplant Patients.

Background/objectives: Our previous retrospective single-center cohort study found, at 3-year follow-up, a trend toward low tacrolimus trough levels and an increased risk of de novo donor-specific anti-HLA antibodies (DSAs) and of antibody-mediated rejection (ABMR) in CYP3A5-expressing patients. Determining CYP3A5-expression status immediately after renal transplant would allow early genotype-based dosage adjustment of tacrolimus and might prevent the occurrence of de novo DSAs and ABMR, improving transplant outcome.

Methods: 160 renal allograft recipients who underwent renal transplant at the University Hospital Essen between May 2019 and May 2022 were genotyped for the rs776746 polymorphism within the first two weeks after transplant, and genotype-based dose adjustment of tacrolimus was performed for the follow-up of 2 years.

The single nucleotide polymorphism rs4986790 (c.896A>G) in the gene as a protective factor in corona virus disease 2019 (COVID-19).

Background And Aims: 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.

Single-Nucleotide Polymorphism in Genes Encoding G Protein Subunits and Increase the Risk of Cardiovascular Morbidity among Patients Undergoing Renal Replacement Therapy.

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 c.825C > T, -695/-694GC > TT, and c.

Influence of the Single Nucleotide Polymorphisms rs12252 and rs34481144 in on the Antibody Response after Vaccination against COVID-19.

The COVID-19 mRNA vaccine is the first mRNA vaccine approved for human administration by both the U.S. Food and Drug Administration and the European Medicines Agency.

Characteristics and Long-Term Outcome of 535 Patients with Autoimmune Hepatitis-The 20-Year Experience of a High-Volume Tertiary Center.

Autoimmune hepatitis (AIH) is a complex and progressive inflammatory liver disease characterized by immune-mediated destruction of the liver parenchyma, hypergammaglobulinemia, the presence of circulating autoantibodies, and good response to immunosuppressive therapy. Since the prevalence of AIH is relatively rare, data on the clinical course and the long-term outcome are scarce. We retrospectively analyzed the data of 535 well-documented AIH patients treated at the University Hospital Essen between 2000 and 2020.

CC Genotype of GNAS c.393C>T (rs7121) Polymorphism Has a Protective Effect against Development of BK Viremia and BKV-Associated Nephropathy after Renal Transplant.

The GNAS gene encodes the alpha-subunit of the stimulatory G-protein (Gαs) in humans and mice. The single-nucleotide polymorphism of GNAS, c.393C>T, is associated with an elevated production of Gαs and an increased formation of cyclic adenosine monophosphate (cAMP).

c.825c>T polymorphism influences T-cell but not antibody response following vaccination with the mRNA-1273 vaccine.

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.

GNB3 c.825C>T (rs5443) Polymorphism and Risk of Acute Cardiovascular Events after Renal Allograft Transplant.

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.

The c.825CT (rs5443) polymorphism and protection against fatal outcome of corona virus disease 2019 (COVID-19).

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 , 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. We analyzed the influence of demographics, pre-existing disorders, laboratory parameters at the time of hospitalization, and rs5443 genotype in a comprehensive cohort (N = 1570) on the outcome of COVID-19.

Individuals With Weaker Antibody Responses After Booster Immunization Are Prone to Omicron Breakthrough Infections.

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.

Development of De Novo Donor-specific HLA Antibodies and AMR in Renal Transplant Patients Depends on CYP3A5 Genotype.

Background: The single-nucleotide polymorphism CYP3A5 rs776746 is related to a reduction in the metabolizing activity of the CYP3A5 enzyme. People carrying at least one copy of the wild-type allele, defined as CYP3A5 expressers, exhibit higher clearance and lower trough concentrations of tacrolimus than homozygous nonexpressers, and this difference may affect alloimmunization and allograft function.

Methods: We retrospectively studied 400 kidney transplant recipients treated with a tacrolimus-based immunosuppression regimen to detect CYP3A5 genotype, de novo formation of HLA antibodies and donor-specific antibodies (DSAs), and clinical outcome up to 5 y after transplant.

ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19.

Objectives: The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs.

Polymorphisms and Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection: A German Case-Control Study.

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.

The influence of IFITM3 polymorphisms on susceptibility to SARS-CoV-2 infection and severity of COVID-19.

Background And Aims: The interferon-induced transmembrane protein 3 (IFITM3) plays an important role in the adaptive and innate immune response by inhibiting viral membrane hemifusion between the host and viral cell cytoplasm. Single nucleotide polymorphisms (SNPs) in the gene IFITM3 have been associated with susceptibility and severity of influenza or other viral infections. We aimed to analyze the role of SNPs in the gene IFITM3 in SARS-CoV-2 infection.

NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis.

Metamizole is a widely prescribed NSAID with excellent analgesic and antipyretic properties. Although very effective, it is banned in some countries because of the risk for severe agranulocytosis. We here describe three patients with metamizole-associated agranulocytosis.

Characterization of the G protein-coupled receptor kinase 6 promoter reveals a functional CREB binding site.

Background: G protein-coupled receptor kinase 6 (GRK6) is part of the G protein-coupled receptor kinase family, whose members act as key regulators of seven-transmembrane receptor signalling. GRK6 seems to play a role in regulation of inflammatory processes, but mechanisms of transcriptional regulation of GRK6 expression in inflammatory cell lines have not been characterized. Protein kinase C (PKC) signalling is also involved in inflammatory regulation and an impact of PKC activation on GRK6 protein expression was described previously.

Lack of association of common polymorphisms linked to empathic behavior with self-reported trait empathy in healthy volunteers.

Background: In a previously specified sample of 421 healthy subjects, we found associations of a common oxytocin receptor (OXTR) polymorphism with self-reported trait empathy. In this study, we used this sample to explore polymorphisms in other genes which have been frequently linked to empathic behavior for associations with self-reported trait empathy: CD38 (CD38), involved in oxytocin secretion, the serotonin transporter (SLC6A4), the Catechol-O-Methyltransferase (COMT) and the corticotropin releasing hormone receptor 1 (CRHR1).

Methods: We genotyped our sample for the following common polymorphisms: rs3796863 in the CD38 gene, 5-HTTLPR in the SLC6A4 gene, rs4680 in the COMT gene and rs242924 in the CRHR1 gene.

Genetic variations in G-protein signal pathways influence progression of coronary artery calcification: Results from the Heinz Nixdorf Recall study.

Background And Aims: Coronary artery calcification (CAC) is one of the most sensitive and specific markers of coronary atherosclerosis and believed to be heritable. We hypothesized that functionally relevant single-nucleotide polymorphisms (SNPs) in the G-protein signal pathway, which have been previously related to coronary artery disease, are associated with CAC progression.

Methods: 3108 participants from the Heinz Nixdorf Recall study with CAC measurements at both baseline (CACb) and 5-year follow-up (CAC5y) were included.

Major Adverse Kidney Events Are Associated with the Aquaporin 5 -1364A/C Promoter Polymorphism in Sepsis: A Prospective Validation Study.

Since the functionally important -1364A/C single nucleotide promoter polymorphism alters key mechanisms of inflammation and survival in sepsis, it may affect the risk of an acute kidney injury. Accordingly, we tested the hypothesis in septic patients that this polymorphism is associated with major adverse kidney events and also validated its impact on 90-day survival. In this prospective observational monocentric genetic association study 282 septic patients were included and genotyped for the -1364A/C polymorphism (rs3759129).

DNA methylation of a NF-κB binding site in the aquaporin 5 promoter impacts on mortality in sepsis.

Altered aquaporin 5 (AQP5) expression in immune cells impacts on key mechanisms of inflammation and is associated with sepsis survival. Since epigenetic regulation via DNA methylation might contribute to a differential AQP5 expression in sepsis, we tested the hypotheses that DNA methylation of the AQP5 promotor (1) influences AQP5 expression, (2) is associated with the 30-day survival of septic patients, and (3) alters the nuclear transcription factor NF-κB binding. AQP5 mRNA expression was quantified by real-time PCR in whole blood samples of 135 septic patients.

The SNP c.393C>T (rs7121) as a marker for disease progression and survival in cancer.

G-protein receptor signaling plays a key role in multiple signal transduction pathways. Aberrant activity of the stimulatory Gα subunit has been frequently associated with cancer. sequence alterations and conformational changes of Gα can both enhance or diminish its function and change downstream effects of G-protein receptor signaling.

The aquaporin 5 -1364A/C promoter polymorphism impacts on resolution of acute kidney injury in pneumonia evoked ARDS.

Background: Aquaporin 5 (AQP5) expression impacts on cellular water transport, renal function but also on key mechanisms of inflammation and immune cell migration that prevail in sepsis and ARDS. Thus, the functionally relevant AQP5 -1364A/C promoter single nucleotide polymorphism could impact on the development and resolution of acute kidney injury (AKI). Accordingly, we tested the hypothesis that the AQP5 promoter -1364A/C polymorphism is associated with AKI in patients suffering from pneumonia evoked ARDS.

Sex-specific association of a common GNAS polymorphism with self-reported cognitive empathy in healthy volunteers.

Background: In a recent study, we found associations of a common oxytocin receptor (OXTR) polymorphism with inter-individual differences in empathy, especially with emotional empathy in women. Many other studies found specific associations of oxytocin, arginine-vasopressin, serotonin and dopamine receptor gene polymorphisms with various aspects of trait empathy. As all these receptors belong to the guanine-binding protein (G protein) coupled receptor family, it is a reasonable assumption, that alterations in genes encoding G protein subunits also influence the signal transduction in empathy related circuits.

The GRK2 Promoter Is Regulated by Early-Growth Response Transcription Factor EGR-1.

The G-protein-coupled receptor kinase 2 (GRK2) plays a major role in cardiovascular diseases, and its expression is increased in heart failure. However, only little is known about factors being involved in up-regulation of GRK2 expression through transcriptional regulation of its promoter. Since the transcription factor early-growth response 1 (EGR-1) is also up-regulated in patients with heart failure, we tested the hypothesis that EGR-1 regulates GRK2 transcription.