Rapid response to the alpha-1 adrenergic agent phenylephrine in the perioperative period is impacted by genomics and ancestry.
Stephane WenricJanina M JeffThomas JosephMuh-Ching YeeGillian M BelbinAniwaa Owusu ObengStephen B EllisErwin P BottingerOmri GottesmanMatthew A LevinEimear E KennyPublished in: The pharmacogenomics journal (2020)
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.
Keyphrases
- genome wide
- genome wide association study
- blood pressure
- copy number
- end stage renal disease
- minimally invasive
- newly diagnosed
- dna methylation
- coronary artery bypass
- ejection fraction
- genome wide association
- chronic kidney disease
- peritoneal dialysis
- palliative care
- prognostic factors
- healthcare
- mental health
- atrial fibrillation
- gene expression
- hypertensive patients
- skeletal muscle
- artificial intelligence
- intensive care unit
- high resolution
- patients undergoing
- big data
- type diabetes
- drug induced
- heart rate
- mechanical ventilation
- insulin resistance