Nutrigenomics: where are we with genetic and epigenetic markers for disposition and susceptibility?

The revelation of the human genome has enabled scientists to assess the disposition and response of an organism to an environmental stimulus; transcriptomics, proteomics, and metabonomics can each generate such holistic views. Nutrigenomic techniques help researchers elucidate individual responses to nutritional interventions holistically and help with the design of personalized diets adapted to individual needs. Human genetics has revealed insights into health and disease susceptibility and can help differentiate responders from nonresponders in dietary interventions, but the predictive power of single-nucleotide polymorphisms in disease susceptibility genes has so far been limited in terms of helping to foresee a health trajectory. Epigenetics encompasses alterations of genetic material that do not affect the DNA nucleotide sequence; these include DNA methylation patterns, chromatin structure, histone codes, and non-coding small RNAs. DNA methylation is modified particularly around the time of birth; therefore, early-life nutrition may affect health outcomes later in lif

A 3′UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like Kinase 1

BACKGROUND: The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors. METHODS: The coding region, the 5′ and 3′UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3′UTR polymorphism. RESULTS: Four putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3′untranslated region (3′UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele-dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01). CONCLUSION: The present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors

The single nucleotide polymorphism rs4986790 (c.896A>G) in the gene TLR4 as a protective factor in corona virus disease 2019 (COVID-19)

Background and aimsSeveral 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 TLR4 gene to identify a universal marker for preclinical prediction of COVID-19 disease progression.MethodsWe analyzed the influence of demographics, pre-existing conditions, inflammatory parameters at the time of hospitalization, and TLR4 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.ResultsWe 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 TLR4 rs4986790 was found to be a protective factor against COVID-19 disease progression (OR: 0.51, 95% CI: 0.34 - 0.77, p = 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 TLR4 rs4986790 AG/GG genotypes as independent predictors of potential hospitalization and reduction of severe or fatal disease course.ConclusionIn this study, we identified an additional genetic factor that may serve as an invariant predictor of COVID-19 outcome. The TLR4 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

Nutrigenomics: where are we with genetic and epigenetic markers for disposition and susceptibility?

The revelation of the human genome has enabled scientists to assess the disposition and response of an organism to an environmental stimulus; transcriptomics, proteomics, and metabonomics can each generate such holistic views. Nutrigenomic techniques help researchers elucidate individual responses to nutritional interventions holistically and help with the design of personalized diets adapted to individual needs. Human genetics has revealed insights into health and disease susceptibility and can help differentiate responders from nonresponders in dietary interventions, but the predictive power of single-nucleotide polymorphisms in disease susceptibility genes has so far been limited in terms of helping to foresee a health trajectory. Epigenetics encompasses alterations of genetic material that do not affect the DNA nucleotide sequence; these include DNA methylation patterns, chromatin structure, histone codes, and non-coding small RNAs. DNA methylation is modified particularly around the time of birth; therefore, early-life nutrition may affect health outcomes later in life

Na+/H+ exchange and Ca2+ influx

AbstractCell stimulation raises the cytosolic free Ca2+ concentration, [Ca2+]i, and induces activation of Na+/H+ exchange which raises the cytosolic pH, pHj. Recent studies have addressed the question whether Na+/H+ exchange plays a role in Ca2+ influx and, specifically, whether a rise in pHi alone suffices to open Ca2+ channels in the plasma membrane. Artificial cytosolic alkalinization can induce Ca2+ uptake across the plasma membrane of endothelial cells, lymphocytes and smooth muscle cells. Furthermore, inhibition of Na+/H+ exchange reduces aganist-induced Ca2+ influx in endothelial cells and platelets which supports the concept that pHi may regulate the opening of Ca2+ channels in the plasma membrane. Although these findings argue in favour of a role of Na+/H+ exchange in Ca2+ influx, the onset of pHi and Ca2+ rises, measured with fluorescent indicators, suggests that the increase in [Ca2+]i distinctly precedes the increase in pHi. This challenges the concept that alkalinization per se is a sufficient signal for the opening of Ca2+ channels in the plasma membrane