Beyond drugs: the evolution of genes involved in human response to medications.

Proc Biol Sci. 2019 Oct 23;286(1913):20191716

Authors: Fuselli S

Abstract
The genetic variation of our species reflects human demographic history and adaptation to diverse local environments. Part of this genetic variation affects individual responses to exogenous substances, such as food, pollutants and drugs, and plays an important role in drug efficacy and safety. This review provides a synthesis of the evolution of loci implicated in human pharmacological response and metabolism, interpreted within the theoretical framework of population genetics and molecular evolution. In particular, I review and discuss key evolutionary aspects of different pharmacogenes in humans and other species, such as the relationship between the type of substrates and rate of evolution; the selective pressure exerted by landscape variables or dietary habits; expected and observed patterns of rare genetic variation. Finally, I discuss how this knowledge can be translated directly or after the implementation of specific studies, into practical guidelines.

PMID: 31640517 [PubMed - in process]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/10/23

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16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/10/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Precision treatment in colorectal cancer: Now and the future.

JGH Open. 2019 Oct;3(5):361-369

Authors: Yau TO

Abstract
Until recently, a one-drug-fits-all model was applied to every patient diagnosed with the same condition. But not every condition is the same, and this has led to many cases of ineffective treatment. Pharmacogenetics is increasingly used to stratify patients for precision medicine treatments, for instance, the UGT1A1*28 polymorphism as a dosage indicator for the use of irinotecan as well as epidermal growth factor receptor (EGFR) immunohistochemistry and KRAS Proto-Oncogene (KRAS) exon 2 mutation tests for determining the likelihood of treatment response to cetuximab or panitumumab treatment in metastatic colorectal cancer (CRC). The other molecular subtypes, such as KRAS exon 3/4, B-Raf Proto-Oncogene, NRAF, PIK3CA, and PETN, were also reported as potential new pharmacogenetic targets for the current and the newly discovered anticancer drugs. In addition to next-generation sequencing (NGS), primary tumor cells for in vivo and in vitro drug screening, imaging biomarker 3'-Deoxy-3'-18F-fluorothymidine positron emission tomography, and circulating tumor DNA (ctDNA) detection methods are being developed and may represent the future direction of precision medicine. This review will discuss the current environment of precision medicine, including clinically approved targeted therapies, the latest potential therapeutic agents, and the ongoing pharmacogenetic trials for CRC patients.

PMID: 31633039 [PubMed]

Knowledge And Attitudes Of Pharmacy Students Towards Pharmacogenomics Among Universities In Jordan And West Bank Of Palestine.

Pharmgenomics Pers Med. 2019;12:247-255

Authors: Jarrar Y, Mosleh R, Hawash M, Jarrar Q

Abstract
Background: Testing by pharmacogenomics (PGx) aims to reduce the side-effects of medicines and to optimize therapy.
Aim: To ascertain the knowledge and attitudes towards PGx among pharmacy students in Jordan and West Bank of Palestine (WBP).
Methods: This cross-sectional study focused on pharmacy students from five universities in Jordan and WBP. Students were asked to answer an online survey comprising 30-closed ended questions measuring the knowledge and attitudes towards PGx.
Results: The total number of respondents to the questionnaire was 466. Most (96.1%) respondents knew that genetic variations can affect the drug response. Most students stated that the total number of lectures mentioning PGx was fewer than three. Most (>80%) respondents answered that they knew that human genetics can affect the response, inter-individual variation, and ethnic variations in the drug response. However, their knowledge about US Food and Drug Administration recommendations regarding PGx testing of commonly used drugs was weak. Also, 60.3% of respondents stated that the information they received about PGx was insufficient. Most (>92.7%) students wished to know more about PGx and believed that PGx is helpful in choosing the appropriate drug.
Conclusion: Pharmacy students had fair knowledge and good attitudes towards PGx. These factors could aid application of PGx in clinical practice in Jordan and WBP.

PMID: 31632127 [PubMed]

Aberrant DNA methylation of PAX1, SOX1 and ZNF582 genes as potential biomarkers for esophageal squamous cell carcinoma.

Biomed Pharmacother. 2019 Oct 16;120:109488

Authors: Tang L, Liou YL, Wan ZR, Tang J, Zhou Y, Zhuang W, Wang G

Abstract
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly invasive malignant tumor and the majority of patients have advanced stage of ESCC at diagnosis with poor outcome. Identification of sensitive and specific biomarkers for early screening of ESCC is critical for improving patient overall survival.
METHODS: Pyrosequencing was used to determine the magnitude of DNA methylation on the selected regions PAX1 (paired box gene1), SOX1(sex determining region Y-box-1), and ZNF582 (zinc finger protein 582) in ESCC.
RESULTS: The methylation levels ofPAX1, SOX1, and ZNF582 genes were significantly higher in the cancerous tissues compared to those in the non-cancerous (all P < 0.0001). The accuracy, sensitivity and specificity of PAX1 methylation for the detection of cancer were respectively 0.754, 96.0% and 51.4%; for SOX1 which were 0.781, 89.2% and 59.5%; for ZNF582 which were 0.898, 93.2% and 75.7%. Most importantly, both the sensitivity and specificity of ZNF582 methylation testing achieved 100% in female ESCC patients. Hypermethylation of PAX1/SOX1/ZNF582 exhibited as an independent risk factor for ESCC development. In addition, ZNF582 methylation level in tumor tissue from the female patients was higher than that from male patients, and it was higher in the moderate and poor differentiated tumors compared to that in well-differentiated tumors. SOX1 methylation level was significantly higher in tumors located in the upper region than those located in the middle or lower regions.
CONCLUSION: The methylation levels ofPAX1, SOX1 and ZNF582 genes were all higher in cancer tissues than in paired-adjacent and normal tissues, suggesting that detection of PAX1/SOX1/ZNF582 methylation status may serve as a promising biomarker for ESCC screening and diagnosis.

PMID: 31629253 [PubMed - as supplied by publisher]

Dose-Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs.

Clin Pharmacol Ther. 2019 Oct 18;:

Authors: Mori D, Kimoto E, Rago B, Kondo Y, King-Ahmad A, Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M, Rodrigues AD, Muto C, Furihata K, Sugiyama Y, Kusuhara H

Abstract
To address the most appropriate endogenous biomarker for drug-drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor (rifampicin, 150, 300 and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate-3-glucuronide, glycochenodeoxycholate-3-sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose-dependent change in area under the plasma concentration-time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC0-24h between the endogenous compounds and the probe drugs, and by non-linear regression analysis (AUCR-1 versus rifampicin plasma Cmax ) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B-mediated drug-drug interaction risk assessment approaches based on agency guidelines in early clinical trials.

PMID: 31628668 [PubMed - as supplied by publisher]

Influence of CYP2B6 activity score on the pharmacokinetics and safety of single dose efavirenz in healthy volunteers.

Pharmacogenomics J. 2019 Oct 18;:

Authors: Zubiaur P, Saiz-Rodríguez M, Ochoa D, Belmonte C, Román M, Mejía G, Martín-Vilchez S, Abad-Santos F

Abstract
Efavirenz is a non-nucleoside reverse transcriptase inhibitor used as first-line therapy for the treatment of HIV infection. Cytochrome P450 (CYP) CYP2B6 G516T (rs3745274) is a well-known predictor of efavirenz disposition. Dose adjustment based on G516T variant has been shown to be beneficial. However, this variant cannot explain the entire variability of efavirenz pharmacokinetics. In this study, we evaluated the influence of 11 single-nucleotide polymorphisms (SNPs) in CYP2B6, CYP2A6, CYP3A and ABCB1 (ATP-binding cassette sub-family B member 1) on the pharmacokinetics and safety of efavirenz after single oral dose administration to 47 healthy volunteers. We designed and validated a CYP2B6 activity score model based on two CYP2B6 SNPs (G516T and rs4803419) that predicted efavirenz disposition better than G516T alone.

PMID: 31628422 [PubMed - as supplied by publisher]

Effects and Safety of an Oral Adsorbent on Chronic Kidney Disease Progression: A Systematic Review and Meta-Analysis.

J Clin Med. 2019 Oct 17;8(10):

Authors: Chen YC, Wu MY, Hu PJ, Chen TT, Shen WC, Chang WC, Wu MS

Abstract
BACKGROUND: AST-120 (Kremezin), which is an oral spherical carbon adsorbent, has been reported to have the potential for retarding disease progression in patients with chronic kidney disease. We aimed to evaluate its efficacy and safety in this study.
METHODS: We systematically searched for randomized controlled trials published in PubMed, Embase, and Cochrane databases. The primary outcomes were the renal outcome and all-cause mortality, and the change in serum indoxyl sulfate (IS) levels. The safety outcome was also evaluated in terms of reported major adverse events. A random-effects model was used when heterogeneity was expected.
RESULTS: Eight studies providing data for 3349 patients were included in the meta-analysis. The risk ratio of renal outcome and all-cause mortality were 0.97 (95% CI: 0.88-1.07; 6 trials) and 0.94 (0.73-1.20; 5 trials), respectively. Furthermore, the weighted mean change in IS levels from baseline to the end of the study was -0.28 mg/dL (95% CI: -0.46 to -0.11; 4 trials).
CONCLUSIONS: This study provides evidence that AST-120 can effectively lower IS levels but still controversial in terms of slowing disease progression and all-cause mortality. Except for dermatological events, the incidence of adverse events did not differ significantly between the AST-120 and placebo groups.

PMID: 31627462 [PubMed]

[Perspectives of the use of pharmacogenetic tests in neurology and psychiatry].

Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(9):131-135

Authors: Kostyuk GP, Zakharova NV, Reznik AM, Surkova EI, Ilinsky VV

Abstract
The review is devoted to the analysis of the current state of pharmacogenetic research and their use in psychiatric practice. The main genes responsible for the pharmacodynamics and pharmacokinetics of drugs used in psychiatry are listed. Foreign pharmacogenetic clinical recommendations and progress on their implementation in medical practice in various countries of Europe and the USA are analyzed. The need to create Russian clinical guidelines on pharmacogenomics to improve the effectiveness of patient care and to implement a personalized approach to therapy is discussed.

PMID: 31626230 [PubMed - in process]

PREFACE for the special issue of xenobiotica on "pharmacogenetics of drug metabolism".

Xenobiotica. 2019 Oct 18;:1-4

Authors: Mitchell S, Steventon G

PMID: 31625424 [PubMed - as supplied by publisher]

Dissecting the m6A methylation affection on afatinib resistance in non-small cell lung cancer.

Pharmacogenomics J. 2019 Oct 17;:

Authors: Meng Q, Wang S, Zhou S, Liu H, Ma X, Zhou X, Liu H, Xu C, Jiang W

Abstract
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer deaths. Afatinib is the first-line anti-cancer agent for treatment of NSCLC. However, unexpected resistance has been a major obstacle for its clinical efficacy. In this study, we dissected afatinib resistance from the perspective of N6-Methyladenosine (m6A) modification. First, we depicted the m6A modification profiles for the afatinib resistant and sensitive NSCLC cell lines (H1299 and A549). We found that the sum enrichment scores of the resistant cell line (H1299) was much higher than that of the sensitive cell line (A549). Next, we identified the functionally m6A-modified genes, which were the intersection of the differentially m6A methylated genes and the differentially expressed genes between H1299 and A549, as well as negative correlation between m6A modification levels and gene expression levels. In addition, functional enrichment analysis of the functionally m6A-modified genes indicated that m6A methylation might modify cell cycle to affect afatinib response. Furthermore, the functionally m6A-modified genes were over-represented in the putative drug resistance-associated genes and the FDA-approved drug targets, and had significantly higher average degree and clustering coefficient than other genes in protein-protein interaction (PPI) network. We also identified five network modules, which were all related to drug resistance functions. Finally, survival analysis demonstrated that m6A modification could affect prognosis of NSCLC patients. In conclusion, we conducted a first attempt to dissect m6A methylation affection on afatinib resistance in NSCLC, and brought inspiration for the study of epigenetic roles in drug resistance.

PMID: 31624334 [PubMed - as supplied by publisher]

Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?

Pharmacogenomics J. 2019 Oct 17;:

Authors: van Eijk RPA, Eijkemans MJC, Nikolakopoulos S, Jansen MD, Westeneng HJ, van Eijk KR, van der Spek RAA, van Vugt JJFA, Piepers S, Groeneveld GJ, Veldink JH, van den Berg LH, van Es MA

Abstract
Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.

PMID: 31624333 [PubMed - as supplied by publisher]

ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide.

Pharmacogenomics J. 2019 Oct 17;:

Authors: Malmström A, Łysiak M, Åkesson L, Jakobsen I, Mudaisi M, Milos P, Hallbeck M, Fomichov V, Broholm H, Grunnet K, Poulsen HS, Bratthäll C, Strandeus M, Papagiannopoulou A, Stenmark-Askmalm M, Green H, Söderkvist P

Abstract
Standard treatment for glioblastoma (GBM) patients is surgery and radiochemotherapy (RCT) with temozolomide (TMZ). TMZ is a substrate for ABCB1, a transmembrane drug transporter. It has been suggested that survival for GBM patients receiving TMZ is influenced by different single-nucleotide variants (SNV) of ABCB1. We therefore examined SNV:s of ABCB1, namely 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T and correlated to survival for GBM patients receiving RCT. In a pilot cohort (97 patients) a significant correlation to survival was found for SNV 1199G>A, with median OS for variant G/G patients being 18.2 months versus 11.5 months for A/G (p = 0.012). We found no correlation to survival for the other SNV:s. We then expanded the cohort to 179 patients (expanded cohort) and also included a confirmatory cohort (49 patients) focusing on SNV 1199G>A. Median OS for G/G versus A/G plus A/A was 15.7 and 11.5 months, respectively (p = 0.085) for the expanded cohort and 13.8 versus 16.8 months (p = 0.19) for the confirmatory. In conclusion, in patients with GBM receiving RCT with TMZ, no correlation with survival was found for the SNV:s 1236C>T, 2677G>T/A, and 3435C>T of ABCB1. Although the SNV 1199G>A might have some impact, a clinically significant role could not be confirmed.

PMID: 31624332 [PubMed - as supplied by publisher]

Predictive genetic biomarkers for the efficacy of methotrexate in rheumatoid arthritis: a systematic review.

Pharmacogenomics J. 2019 Oct 17;:

Authors: Eektimmerman F, Swen JJ, Madhar MB, Allaart CF, Guchelaar HJ

Abstract
Multiple pharmacogenetic studies investigated the effectiveness of methotrexate. However, due to the use of nonvalidated outcomes, lack of validation or conflicting results it remains unclear if genetic markers can help to predict response to MTX treatment. Therefore, a systematic review was performed. PubMed was searched for articles reporting potential pharmacogenetic biomarkers associated (p < 0.05) with MTX efficacy using the validated endpoints DAS(28), EULAR, or ACR response criteria. The PICO method was used for study selection, and PRISMA guidelines to prepare the report. Thirty-five studies met the inclusion criteria, providing 39 potential genetic biomarkers in 19 genes. After Bonferroni correction, six genetic biomarkers were associated with the efficacy of MTX: ATIC rs7563206; SLC19A1 rs1051266; DHFR rs836788; TYMS rs2244500, rs2847153, and rs3786362 in at least one study. Only SLC19A1 rs1051266 was replicated in an independent cohort and promising for predicting methotrexate efficacy.

PMID: 31624331 [PubMed - as supplied by publisher]

Utilizing a user-centered approach to develop and assess pharmacogenomic clinical decision support for thiopurine methyltransferase.

BMC Med Inform Decis Mak. 2019 Oct 17;19(1):194

Authors: Nguyen KA, Patel H, Haggstrom DA, Zillich AJ, Imperiale TF, Russ AL

Abstract
BACKGROUND: A pharmacogenomic clinical decision support tool (PGx-CDS) for thiopurine medications can help physicians incorporate pharmacogenomic results into prescribing decisions by providing up-to-date, real-time decision support. However, the PGx-CDS user interface may introduce errors and promote alert fatigue. The objective of this study was to develop and evaluate a prototype of a PGx-CDS user interface for thiopurine medications with user-centered design methods.
METHODS: This study had two phases: In phase I, we conducted qualitative interviews to assess providers' information needs. Interview transcripts were analyzed through a combination of inductive and deductive qualitative analysis to develop design requirements for a PGx-CDS user interface. Using these requirements, we developed a user interface prototype and evaluated its usability (phase II).
RESULTS: In total, 14 providers participated: 10 were interviewed in phase I, and seven providers completed usability testing in phase II (3 providers participated in both phases). Most (90%) participants were interested in PGx-CDS systems to help improve medication efficacy and patient safety. Interviews yielded 11 themes sorted into two main categories: 1) health care providers' views on PGx-CDS and 2) important design features for PGx-CDS. We organized these findings into guidance for PGx-CDS content and display. Usability testing of the PGx-CDS prototype showed high provider satisfaction.
CONCLUSION: This is one of the first studies to utilize a user-centered design approach to develop and assess a PGx-CDS interface prototype for Thiopurine Methyltransferase (TPMT). This study provides guidance for the development of a PGx-CDS, and particularly for biomarkers such as TPMT.

PMID: 31623616 [PubMed - in process]

Molecular Imaging of Opioid and Dopamine Systems: Insights Into the Pharmacogenetics of Opioid Use Disorders.

Front Psychiatry. 2019;10:626

Authors: Burns JA, Kroll DS, Feldman DE, Kure Liu C, Manza P, Wiers CE, Volkow ND, Wang GJ

Abstract
Opioid use in the United States has steadily risen since the 1990s, along with staggering increases in addiction and overdose fatalities. With this surge in prescription and illicit opioid abuse, it is paramount to understand the genetic risk factors and neuropsychological effects of opioid use disorder (OUD). Polymorphisms disrupting the opioid and dopamine systems have been associated with increased risk for developing substance use disorders. Molecular imaging studies have revealed how these polymorphisms impact the brain and contribute to cognitive and behavioral differences across individuals. Here, we review the current molecular imaging literature to assess how genetic variations in the opioid and dopamine systems affect function in the brain's reward, cognition, and stress pathways, potentially resulting in vulnerabilities to OUD. Continued research of the functional consequences of genetic variants and corresponding alterations in neural mechanisms will inform prevention and treatment of OUD.

PMID: 31620026 [PubMed]

The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity.

Pharmaceutics. 2019 Oct 15;11(10):

Authors: Simper GS, Gräser LS, Celik AA, Kuhn J, Kunze-Schumacher H, Hò GT, Blasczyk R, Pich A, Bade-Doeding C

Abstract
Drug hypersensitivity reactions that resemble acute immune reactions are linked to certain human leucocyte antigen (HLA) alleles. Severe and life-threatening Stevens Johnson Syndrome and Toxic Epidermal Necrolysis following treatment with the antiepileptic and psychotropic drug Carbamazepine are associated with HLA-B*15:02; whereas carriers of HLA-A*31:01 develop milder symptoms. It is not understood how these immunogenic differences emerge genotype-specific. For HLA-B*15:02 an altered peptide presentation has been described following exposure to the main metabolite of carbamazepine that is binding to certain amino acids in the F pocket of the HLA molecule. The difference in the molecular mechanism of these diseases has not been comprehensively analyzed, yet; and is addressed in this study. Soluble HLA-technology was utilized to examine peptide presentation of HLA-A*31:01 in presence and absence of carbamazepine and its main metabolite and to examine the mode of peptide loading. Proteome analysis of drug-treated and untreated cells was performed. Alterations in sA*31:01-presented peptides after treatment with carbamazepine revealed different half-life times of peptide-HLA- or peptide-drug-HLA complexes. Together with observed changes in the proteome elicited through carbamazepine or its metabolite these results illustrate the mechanistic differences in carbamazepine hypersensitivity for HLA-A*31:01 or B*15:02 patients and constitute the bridge between pharmacology and pharmacogenetics for personalized therapeutics.

PMID: 31618895 [PubMed]

Pharmacogenetic determinants of kidney-associated urinary and serum abnormalities in antiretroviral-treated HIV-positive patients.

Pharmacogenomics J. 2019 Oct 16;:

Authors: Cusato J, Calcagno A, Marinaro L, Avataneo V, DʹAvolio A, Di Perri G, Bonora S

Abstract
Tenofovir disoproxyl fumarate (TDF) has been associated with renal tubular abnormalities, phosphaturia and proteinuria (retinol binding protein, RBP, loss): vitamin D (VD) and PTH affect these markers. Aim was to understand if some single nucleotide polymorphisms (SNPs) were predictors of renal abnormalities in an Italian cohort of HIV-affected patients. DNA was analyzed through real-time PCR, urinary RBP corrected by creatinine (uRBP/Cr). The majority of patients received TDF. Abnormal uRBP/Cr was more frequent in TDF recipients: eGFR <90 mL/min and TDF were predictors in the whole cohort, whereas eGFR <90 mL/min, TDF concentrations and CYP24A1-3999TT in TDF-treated patients. Phosphate levels were higher low VD level patients: age <50 years, CYP27B1 + 2838CC genotype and non-European ancestry were predictors. PTH levels were border-line higher in TDF patients: non-European ancestry, females, TDF, VD levels < 30 ng/mL and SLC28A2-124CT/TT and ABCC2-24CC were predictors. For the first time, SNPs were associated with PTH, phosphate, calcium and tubular dysfunction in HIV-infected patients.

PMID: 31619748 [PubMed - as supplied by publisher]

Muscarinic receptors promote pacemaker fate at the expense of secondary conduction system tissue in zebrafish.

JCI Insight. 2019 Oct 17;4(20):

Authors: Burczyk MS, Burkhalter MD, Tena TC, Grisanti LA, Kauk M, Matysik S, Donow C, Kustermann M, Rothe M, Cui Y, Raad F, Laue S, Moretti A, Zimmermann WH, Wess J, Kühl M, Hoffmann C, Tilley DG, Philipp M

Abstract
Deterioration or inborn malformations of the cardiac conduction system (CCS) interfere with proper impulse propagation in the heart and may lead to sudden cardiac death or heart failure. Patients afflicted with arrhythmia depend on antiarrhythmic medication or invasive therapy, such as pacemaker implantation. An ideal way to treat these patients would be CCS tissue restoration. This, however, requires precise knowledge regarding the molecular mechanisms underlying CCS development. Here, we aimed to identify regulators of CCS development. We performed a compound screen in zebrafish embryos and identified tolterodine, a muscarinic receptor antagonist, as a modifier of CCS development. Tolterodine provoked a lower heart rate, pericardiac edema, and arrhythmia. Blockade of muscarinic M3, but not M2, receptors induced transcriptional changes leading to amplification of sinoatrial cells and loss of atrioventricular identity. Transcriptome data from an engineered human heart muscle model provided additional evidence for the contribution of muscarinic M3 receptors during cardiac progenitor specification and differentiation. Taken together, we found that muscarinic M3 receptors control the CCS already before the heart becomes innervated. Our data indicate that muscarinic receptors maintain a delicate balance between the developing sinoatrial node and the atrioventricular canal, which is probably required to prevent the development of arrhythmia.

PMID: 31619590 [PubMed - in process]