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Rapid response to the Alpha-1 Adrenergic Agent Phenylephrine in the Perioperative Period is Impacted by Genomics and Ancestry

By Stephane Wenric, Janina M. Jeff, Thomas Joseph, Muh-Ching Yee, Gillian M. Belbin, Regeneron Genetics Center, CBIPM Genomics Group, Aniwaa Owusu Obeng, Stephen B Ellis, Erwin P. Bottinger, Omri Gottesman, Matthew A. Levin, Eimear E Kenny

Posted 10 Jun 2019
bioRxiv DOI: 10.1101/664961

Background: The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes that occur during in-patient clinical care. We hypothesized that there is a genetic underpinning to the magnitude of the response to phenylephrine, an alpha1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. Methods: We quantified the response to phenylephrine by determining the delta between the minimum blood pressure (BP) within five minutes before and the maximum BP within five minutes after bolus administration. We then performed a genome-wide association study (GWAS) adjusted for genetic ancestry, demographics, and relevant clinical covariates to investigate genetic factors underlying individual differences systolic BP response to phenylephrine (Delta SBP), as well as mean arterial pressure (Delta MAP) and diastolic BP (Delta DBP), for both the entire study cohort as well as for each of 3 ancestry sub-cohorts; European American (EA), African American (AA), and Hispanic American (HA). Results: 4,317 patients met inclusion criteria, of which 3,699 were genotyped. Average ΔBP values over the entire cohort were Delta SBP= 17 (+- 25) mmHg, Delta MAP = 14 (+- 18) mmHg, Delta DBP = 11(+- 14) mmHg. The largest difference between populations was observed for Delta SBP (Delta SBP EA = 20(+- 24) mmHg; Delta SBP HA = 16 (+- 25) mmHg; Delta SBP AA = 15 (+- 25) mmHg). The differences remained after adjusting for clinical covariates and ancestry (EA vs. HA: Delta SBP, p<0.032; Delta MAP, p<0.021; Delta DBP, p<0.008); (EA vs. AA: Delta SBP, p<5.13x10-5; Delta MAP, p<2.1x10-4; Delta DBP, p<3.3x10-4). GWAS revealed significant associations between loci and BP response in 5 different genome regions (p<5x10-8) in the entire cohort, and suggestive associations in 2 different regions in EAs (p<6x10-8,p<7x10-8). We observed non-random enrichment in association with SBP drug response in 165 loci previously reported to be associated with systolic blood pressure. Finally, we discovered rare variants, rs188427942 and rs147664194 present at ~1% in EAs and rs146535276 present at ~1% in AAs respectively, where patients carrying one copy of these variants show no response to phenylephrine. Conclusions: It is possible to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from routinely collected perioperative data. There are population differences in rapid response to phenylephrine, large effect alleles and novel genes affecting pharmaceutical response, and phenylephrine non-responders, with implications for personalized treatment during surgery.

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