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Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data
BACKGROUND: The alpha-adrenergic agonist phenylephrine is often used to treat hypotension during anesthesia. In clinical situations, low blood pressure may require prompt intervention by intravenous bolus or infusion. Differences in responsiveness to phenylephrine treatment are commonly observed in...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712853/ https://www.ncbi.nlm.nih.gov/pubmed/31455332 http://dx.doi.org/10.1186/s12916-019-1405-7 |
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author | Zhang, Yanfei Poler, S. Mark Li, Jiang Abedi, Vida Pendergrass, Sarah A. Williams, Marc S. Lee, Ming Ta Michael |
author_facet | Zhang, Yanfei Poler, S. Mark Li, Jiang Abedi, Vida Pendergrass, Sarah A. Williams, Marc S. Lee, Ming Ta Michael |
author_sort | Zhang, Yanfei |
collection | PubMed |
description | BACKGROUND: The alpha-adrenergic agonist phenylephrine is often used to treat hypotension during anesthesia. In clinical situations, low blood pressure may require prompt intervention by intravenous bolus or infusion. Differences in responsiveness to phenylephrine treatment are commonly observed in clinical practice. Candidate gene studies indicate genetic variants may contribute to this variable response. METHODS: Pharmacological and physiological data were retrospectively extracted from routine clinical anesthetic records. Response to phenylephrine boluses could not be reliably assessed, so infusion rates were used for analysis. Unsupervised k-means clustering was conducted on clean data containing 4130 patients based on phenylephrine infusion rate and blood pressure parameters, to identify potential phenotypic subtypes. Genome-wide association studies (GWAS) were performed against average infusion rates in two cohorts: phase I (n = 1205) and phase II (n = 329). Top genetic variants identified from the meta-analysis were further examined to see if they could differentiate subgroups identified by k-means clustering. RESULTS: Three subgroups of patients with different response to phenylephrine were clustered and characterized: resistant (high infusion rate yet low mean systolic blood pressure (SBP)), intermediate (low infusion rate and low SBP), and sensitive (low infusion rate with high SBP). Differences among clusters were tabulated to assess for possible confounding influences. Comorbidity hierarchical clustering showed the resistant group had a higher prevalence of confounding factors than the intermediate and sensitive groups although overall prevalence is below 6%. Three loci with P < 1 × 10(−6) were associated with phenylephrine infusion rate. Only rs11572377 with P = 6.09 × 10(−7), a 3′UTR variant of EDN2, encoding a secretory vasoconstricting peptide, could significantly differentiate resistant from sensitive groups (P = 0.015 and 0.018 for phase I and phase II) or resistant from pooled sensitive and intermediate groups (P = 0.047 and 0.018). CONCLUSIONS: Retrospective analysis of electronic anesthetic records data coupled with the genetic data identified genetic variants contributing to variable sensitivity to phenylephrine infusion during anesthesia. Although the identified top gene, EDN2, has robust biological relevance to vasoconstriction by binding to endothelin type A (ET(A)) receptors on arterial smooth muscle cells, further functional as well as replication studies are necessary to confirm this association. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12916-019-1405-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6712853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-67128532019-09-04 Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data Zhang, Yanfei Poler, S. Mark Li, Jiang Abedi, Vida Pendergrass, Sarah A. Williams, Marc S. Lee, Ming Ta Michael BMC Med Research Article BACKGROUND: The alpha-adrenergic agonist phenylephrine is often used to treat hypotension during anesthesia. In clinical situations, low blood pressure may require prompt intervention by intravenous bolus or infusion. Differences in responsiveness to phenylephrine treatment are commonly observed in clinical practice. Candidate gene studies indicate genetic variants may contribute to this variable response. METHODS: Pharmacological and physiological data were retrospectively extracted from routine clinical anesthetic records. Response to phenylephrine boluses could not be reliably assessed, so infusion rates were used for analysis. Unsupervised k-means clustering was conducted on clean data containing 4130 patients based on phenylephrine infusion rate and blood pressure parameters, to identify potential phenotypic subtypes. Genome-wide association studies (GWAS) were performed against average infusion rates in two cohorts: phase I (n = 1205) and phase II (n = 329). Top genetic variants identified from the meta-analysis were further examined to see if they could differentiate subgroups identified by k-means clustering. RESULTS: Three subgroups of patients with different response to phenylephrine were clustered and characterized: resistant (high infusion rate yet low mean systolic blood pressure (SBP)), intermediate (low infusion rate and low SBP), and sensitive (low infusion rate with high SBP). Differences among clusters were tabulated to assess for possible confounding influences. Comorbidity hierarchical clustering showed the resistant group had a higher prevalence of confounding factors than the intermediate and sensitive groups although overall prevalence is below 6%. Three loci with P < 1 × 10(−6) were associated with phenylephrine infusion rate. Only rs11572377 with P = 6.09 × 10(−7), a 3′UTR variant of EDN2, encoding a secretory vasoconstricting peptide, could significantly differentiate resistant from sensitive groups (P = 0.015 and 0.018 for phase I and phase II) or resistant from pooled sensitive and intermediate groups (P = 0.047 and 0.018). CONCLUSIONS: Retrospective analysis of electronic anesthetic records data coupled with the genetic data identified genetic variants contributing to variable sensitivity to phenylephrine infusion during anesthesia. Although the identified top gene, EDN2, has robust biological relevance to vasoconstriction by binding to endothelin type A (ET(A)) receptors on arterial smooth muscle cells, further functional as well as replication studies are necessary to confirm this association. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12916-019-1405-7) contains supplementary material, which is available to authorized users. BioMed Central 2019-08-28 /pmc/articles/PMC6712853/ /pubmed/31455332 http://dx.doi.org/10.1186/s12916-019-1405-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Zhang, Yanfei Poler, S. Mark Li, Jiang Abedi, Vida Pendergrass, Sarah A. Williams, Marc S. Lee, Ming Ta Michael Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data |
title | Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data |
title_full | Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data |
title_fullStr | Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data |
title_full_unstemmed | Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data |
title_short | Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data |
title_sort | dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing ehr data |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712853/ https://www.ncbi.nlm.nih.gov/pubmed/31455332 http://dx.doi.org/10.1186/s12916-019-1405-7 |
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