Impact of medication on blood transcriptome reveals off-target regulations of beta-blockers

Abstract

Background For many drugs, mechanisms of action with regard to desired effects and/or unwanted side effects are only incompletely understood. To investigate possible pleiotropic effects and respective molecular mechanisms, we describe here a catalogue of commonly used drugs and their impact on the blood transcriptome. Methods and results From a population-based cohort in Germany (LIFE-Adult), we collected genome-wide gene-expression data in whole blood using in Illumina HT12v4 micro-arrays (n = 3,378; 19,974 gene expression probes per individual). Expression profiles were correlated with the intake of active substances as assessed by participants’ medication. This resulted in a catalogue of fourteen substances that were identified as associated with differential gene expression for a total of 534 genes. As an independent replication cohort, an observational study of patients with suspected or confirmed stable coronary artery disease (CAD) or myocardial infarction (LIFE-Heart, n = 3,008, 19,966 gene expression probes per individual) was employed. Notably, we were able to replicate differential gene expression for three active substances affecting 80 genes in peripheral blood mononuclear cells (carvedilol: 25; prednisolone: 17; timolol: 38). Additionally, using gene ontology enrichment analysis, we demonstrated for timolol a significant enrichment in 23 pathways, 19 of them including either GPER1 or PDE4B. In the case of carvedilol, we showed that, beside genes with well-established association with hypertension (GPER1, PDE4B and TNFAIP3), the drug also affects genes that are only indirectly linked to hypertension due to their effects on artery walls or their role in lipid biosynthesis. Conclusions Our developed catalogue of blood gene expressions profiles affected by medication can be used to support both, drug repurposing and the identification of possible off-target effects.

Shared Heritability of Blood Pressure and Pulse Wave Velocity: Insights From the STANISLAS Cohort

“…Furthermore, using Mendelian randomization, the authors identified a bidirectional causal relationship between BP and arterial stiffness. 8 However, Rode et al 14 showed that PWV shared a common genetic architecture with BP although the Mendelian randomization analyses conducted on this cohort suggested that arterial stiffness was a consequence rather than a cause of increased BP. As only 2 studies are available, with some conflicting results, additional data using Mendelian randomization may be needed to better ascertain the existence and direction of causality linking BP and arterial stiffness.…”

“…In our study, PWV and SBP showed higher phenotypic correlation, albeit with few genetic codeterminants, whereas PWV and DBP showed more moderate phenotypic correlation (although remained <0.30) but with higher genetic codeterminants. There is evidence of a positive correlation between hypertension and arterial stiffness, 14,25 although the potential genetic link between BP and PWV has been sparsely investigated until recently. Cecelja et al 8 identified >50% of shared genes between BP and PWV when assessing bivariate heritability, although accounted for only a small proportion of the total phenotypic correlation.…”

“…11 Although elevated BP and higher PWV are associated with increased risk factors of cardiovascular diseases and are often clinically related and phenotypically correlated, only sparse studies have investigated the potential genetic correlation between these risk factors. 8,14 The STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort is a longitudinal transgenerational study from the Nancy region of France characterized by a familial structure and long follow-up (up to 23 years). In this cohort, individuals underwent an extensive cardiovascular evaluation, including PWV assessment and ambulatory BP monitoring.…”

Benefits of combined exercise training on arterial stiffness and blood pressure in spontaneously hypertensive rats treated or not with dexamethasone

“…In addition, combined training reduced estimated PWV in SHR, which was a very positive response, since arterial stiffness is considered an important marker of vessel health, an indicative of subclinical organ damage and predictor for the future cardiovascular events (Scuteri et al, 2020;Shchetynska-Marinova et al, 2021). Clinical measurement of PWV has been suggested to early control the development of arterial stiffness, in both patients with increased cardiovascular risk and the general population (Jannasz et al, 2019), since arterial stiffness may be independent of the BP values (Celik et al, 2017;Guers et al, 2019;Rode et al, 2020). There are some metaanalyzes comparing the effects of different types of exercise (aerobic, resistance, combined and high intensity interval training) on PWV, however they include hypertensive and normotensive individuals (Martinez-Vizcaino et al, 2019), which challenge the interpretation of the results.…”

Genomes in clinical care

“…Third, there is significant variability of transcriptome profiles depending on nutrition 37 , infection 38 , medication 39 , sex 40,41 , and age 42 . This variability may limit current global RNA data analysis in the diagnostic context.…”