Rapid response to the alpha-1 adrenergic agent phenylephrine in the perioperative period is impacted by genomics and ancestry.
Adrenergic Agents
/ therapeutic use
Black or African American
/ genetics
Blood Pressure
/ drug effects
Female
Genome-Wide Association Study
/ methods
Genomics
/ methods
Humans
Male
Middle Aged
Perioperative Period
/ methods
Phenotype
Phenylephrine
/ therapeutic use
Polymorphism, Single Nucleotide
/ genetics
White People
/ genetics
Journal
The pharmacogenomics journal
ISSN: 1473-1150
Titre abrégé: Pharmacogenomics J
Pays: United States
ID NLM: 101083949
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
01
12
2019
accepted:
05
10
2020
revised:
21
08
2020
pubmed:
11
11
2020
medline:
13
1
2022
entrez:
10
11
2020
Statut:
ppublish
Résumé
The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups: European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3% increase, p value < 6e-08 and 22.9% increase, p value < 5e-05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.
Identifiants
pubmed: 33168928
doi: 10.1038/s41397-020-00194-5
pii: 10.1038/s41397-020-00194-5
pmc: PMC7997806
doi:
Substances chimiques
Adrenergic Agents
0
Phenylephrine
1WS297W6MV
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
174-189Subventions
Organisme : NHGRI NIH HHS
ID : UM1HG0089001
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG009610
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01HG109391
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01HG009080
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL104608
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG009080
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01HG009610
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG008701
Pays : United States
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