The field of pharmacogenomics (PGx) is gradually shifting from the reactive testing of single genes toward the proactive testing of multiple genes to improve treatment outcomes, reduce adverse ...events, and decrease the burden of unnecessary costs for healthcare systems. Despite the progress in the field of pharmacogenomics, its implementation into routine care has been slow due to several barriers. However, in recent years, the number of studies on the implementation of PGx has increased, all providing a wealth of knowledge on different solutions for overcoming the obstacles that have been emphasized over the past years. This review focuses on some of the challenges faced by these initiatives, the solutions and different approaches for testing that they suggest, and the evidence that they provide regarding the benefits of preemptive PGx testing.
Much of the inter-individual variability in drug efficacy and risk of adverse reactions is due to polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics or ...immunological responses. Pharmacogenetic research has identified a multitude of gene-drug response associations, which have resulted in genetically guided treatment and dosing decisions to yield a higher success rate of pharmacological treatment. The rapid technological developments for genetic analyses reveal that the number of genetic variants with importance for drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to millions of rare mutations. Here, we review the evolutionary background of genetic polymorphisms in drug-metabolizing enzymes, provide some important examples of current use of pharmacogenomic biomarkers, and give an update of germline and somatic genome biomarkers that are in use in drug development and clinical practice. We also discuss the current technology development with emphasis on complex genetic loci, review current initiatives for validation of pharmacogenomic biomarkers, and present scenarios for the future taking rare genetic variants into account for a true personalized genetically guided drug prescription. We conclude that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology. However, the routine use of pharmacogenomic biomarkers in clinical practice in other therapeutic areas is currently sparse and the prospects of its future implementation are being scrutinized by different international consortia.
SARS-CoV-2 infection has a risk to develop into life-threatening COVID-19 disease. Whereas age, hypertension, and chronic inflammatory conditions are risk factors, underlying host factors and markers ...for disease severity, e.g. requiring intensive care unit (ICU) treatment, remain poorly defined. To this end, we longitudinally profiled blood inflammation markers, antibodies, and 101 plasma proteins of hospitalized COVID-19 patients who did or did not require ICU admission. While essentially all patients displayed SARS-CoV-2-specific antibodies and virus-neutralization capacity within 12-15 days, a rapid, mostly transient upregulation of selective inflammatory markers including IL-6, CXCL10, CXCL11, IFNγ, IL-10, and monocyte-attracting CCL2, CCL7 and CCL8, was particularly evident in ICU patients. In addition, there was consistent and sustained upregulation of apoptosis-associated proteins CASP8, TNFSF14, HGF, and TGFB1, with HGF discriminating between ICU and non-ICU cohorts. Thus, COVID-19 is associated with a selective inflammatory milieu within which the apoptotic pathway is a cardinal feature with potential to aid risk-based patient stratification.
Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a ...higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10
, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10
, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10
, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10
, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10
, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors.
COVID-19 pandemic has led to overloading of health systems all over the world. For reliable risk stratification, knowledge on factors predisposing to SARS-CoV-2 infection and to severe COVID-19 ...disease course is needed for decision-making at the individual, provider, and government levels. Data to identify these factors should be easily obtainable.
Retrospective cohort study of nationwide e-health databases in Estonia. We used longitudinal health records from 66,295 people tested positive for SARS-CoV-2 RNA from 26 February 2020 to 28 February 2021 and 254,958 randomly selected controls from the reference population with no known history of SARS-CoV-2 infection or clinical COVID-19 diagnosis (case to control ratio 1:4) to predict risk factors of infection and severe course of COVID-19. We analysed sociodemographic and health characteristics of study participants. The SARS-CoV-2 infection risk was slightly higher among women, and was higher among those with comorbid conditions or obesity. Dementia (RRR 3.77, 95%CI 3.30⎼4.31), renal disease (RRR 1.88, 95%CI 1.56⎼2.26), and cerebrovascular disease (RRR 1.81, 95%CI 1.64⎼2.00) increased the risk of infection. Of all SARS-CoV-2 infected people, 92% had a non-severe disease course, 4.8% severe disease (requiring hospitalisation), 1.7% critical disease (needing intensive care), and 1.5% died. Male sex, increasing age and comorbid burden contributed significantly to more severe COVID-19, and the strength of association for male sex increased with the increasing severity of COVID-19 outcome. The strongest contributors to critical illness (expressed as RRR with 95% CI) were renal disease (7.71, 4.71⎼12.62), the history of previous myocardial infarction (3.54, 2.49⎼5.02) and obesity (3.56, 2.82⎼4.49). The strongest contributors to a lethal outcome were renal disease (6.48, 3.74⎼11.23), cancer (3.81, 3.06⎼4.75), liver disease (3.51, 1.36⎼9.02) and cerebrovascular disease (3.00, 2.31⎼3.89).
We found divergent effect of age and gender on infection risk and severity of COVID-19. Age and gender did not contribute substantially to infection risk, but did so for the risk of severe disease Co-morbid health conditions, especially those affecting renin-angiotensin system, had an impact on both the risk of infection and severe disease course. Age and male sex had the most significant impact on the risk of severe COVID-19. Taking into account the role of ACE2 receptors in the pathogenesis of SARS-CoV-2 infection, as well as its modulating action on the renin-angiotensin system in cardiovascular and renal diseases, further research is needed to investigate the influence of hormonal status on ACE2 expression in different tissues, which may be the basis for the development of COVID-19 therapies.
The Estonian Biobank cohort is a volunteer-based sample of the Estonian resident adult population (aged ≥18 years). The current number of participants-close to 52000--represents a large proportion, ...5%, of the Estonian adult population, making it ideally suited to population-based studies. General practitioners (GPs) and medical personnel in the special recruitment offices have recruited participants throughout the country. At baseline, the GPs performed a standardized health examination of the participants, who also donated blood samples for DNA, white blood cells and plasma tests and filled out a 16-module questionnaire on health-related topics such as lifestyle, diet and clinical diagnoses described in WHO ICD-10. A significant part of the cohort has whole genome sequencing (100), genome-wide single nucleotide polymorphism (SNP) array data (20 000) and/or NMR metabolome data (11 000) available (http://www.geenivaramu.ee/for-scientists/data-release/). The data are continuously updated through periodical linking to national electronic databases and registries. A part of the cohort has been re-contacted for follow-up purposes and resampling, and targeted invitations are possible for specific purposes, for example people with a specific diagnosis. The Estonian Genome Center of the University of Tartu is actively collaborating with many universities, research institutes and consortia and encourages fellow scientists worldwide to co-initiate new academic or industrial joint projects with us.
The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind ...the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP -previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P = 1.80 × 10
). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P = 5.36 × 10
) and waist circumference (P = 5.21 × 10
). The previously identified type 2 diabetes-associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P = 2.24 × 10
). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P = 7.81 × 10
). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.
Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on ...disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.
Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a ...first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the
genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.
Age‐related changes at the cellular level include the dysregulation of metabolic and signaling pathways. Analyses of blood leukocytes have revealed a set of alterations that collectively lower their ...ability to fight infections and resolve inflammation later in life. We studied the transcriptomic, epigenetic, and metabolomic profiles of monocytes extracted from younger adults and individuals over the age of 65 years to map major age‐dependent changes in their cellular physiology. We found that the monocytes from older persons displayed a decrease in the expression of ribosomal and mitochondrial protein genes and exhibited hypomethylation at the HLA class I locus. Additionally, we found elevated gene expression associated with cell motility, including the CX3CR1 and ARID5B genes, which have been associated with the development of atherosclerosis. Furthermore, the downregulation of two genes, PLA2G4B and ALOX15B, which belong to the arachidonic acid metabolism pathway involved in phosphatidylcholine conversion to anti‐inflammatory lipoxins, correlated with increased phosphatidylcholine content in monocytes from older individuals. We found age‐related changes in monocyte metabolic fitness, including reduced mitochondrial function and increased glycose consumption without the capacity to upregulate it during increased metabolic needs, and signs of increased oxidative stress and DNA damage. In conclusion, our results complement existing findings and elucidate the metabolic alterations that occur in monocytes during aging.
We find age‐related changes in monocyte metabolic fitness, including increased glucose consumption without the capacity to upregulate it during increased metabolic needs, and reduced mitochondrial function together with signs of increased oxidative stress and DNA damage. Downregulation of PLA2G4B and ALOX15B expression correlates with increased phosphatidylcholine content in monocytes from older individuals and possibly lower synthesis of anti‐inflammatory lipoxins.
PDF
