Rapid response to the alpha-1 adrenergic agent phenylephrine in the perioperative period is impacted by genomics and ancestry

Abstract

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.

Fig. 1. Data capture schema & Inclusion/Exclusion criteria.

A Data capture schema. The raw phenotype is captured during surgery within a 10 min interval. Additional procedure-related information, as well as general patient-related variables, including genomic data, are combined through the analysis pipeline. B Inclusion/exclusion criteria. From an initial cohort of 19,685 iGAS patients matched to 55,104 procedures, the sequential exclusion criteria and filtering steps reduced the number of patients included in the study to 4317 comprising 1217 African Americans, 1387 European Americans, and 1713 Hispanic/Latinos.

Fig. 2. Drug response difference between populations.

Cumulative distribution function for Δ Systolic Blood Pressure for African-Americans (in red), European Americans (in green), and Hispanic/Latinos (in blue). Average values for Δ SBP for AA, EA, HA are 15.31 mmHg (SE ± 0.71), 20.05 mmHg (SE ± 0.66), and 16.35 mmHg (SE ± 0.6) respectively.

Fig. 3. Manhattan plots and QQ plots of the genome-wide association studies.

A GWAS performed on Δ SBP with the whole cohort. The red horizontal line denotes the genome-wide significance threshold for p-values (5e−8) while the blue horizontal line denotes a p-value threshold of 1e−5. The top SNP is rs145337816, located on chromosome 5, at locus 117211218 (in hg19 coordinates). The minor allele frequency is 0.46%, the imputation info score is 0.909. The association p-value is 2.02e−8. Lambda-gc = 1.0059. B GWAS performed on Δ SBP with European Americans. The top SNP is rs188427942, located on chromosome 5, at locus 122900413 (in hg19 coordinates). The minor allele frequency is 1.16 % in EA (0.57% in the whole cohort), the imputation info score is 0.759. The association p-value is 5.26e−8. Lambda-gc = 0.9976. C performed on Δ SBP with Hispanic/Latinos. The top SNP is rs6657443, located on chromosome 1, at locus 209189265 (in hg19 coordinates). The minor allele frequency is 7.63 % in HA (8.83% in the whole cohort), the imputation info score is 0.948. The association p-value is 7.62e−9. Lambda-gc = 1.0027.

Fig. 4. Locus Zoom plots showing patterns of linkage disequilibrium around top SNPs.

A Patterns of LD around the top SNP rs145337816 for the GWAS performed on Δ SBP with the whole cohort. B Patterns of LD around the top SNP rs188427942 for the GWAS performed on Δ SBP with European Americans. C Patterns of LD around SNP rs147664194 for the GWAS performed on Δ SBP with European Americans. D Patterns of LD around the top SNPs for the GWAS performed on Δ SBP with Hispanic/Latinos.

Fig. 5. Association enrichment in systolic blood pressure genes.

The four plots show the distribution of the number of SNP associations with a p value lower than 1e−3, when randomly selecting 165 genome regions (1000 permutations) for the four different population groups (the whole cohort in black, European Americans in green, African Americans in red, Hispanic/Latinos in blue). The vertical bars correspond to the number of genes out of the 165 genes identified in the UKBB cohort to be associated with systolic blood pressure which obtain a p value lower than 1e−3 when looking for association with Δ SBP in our four cohorts. The 165 systolic blood pressure genes are nominally enriched in association with Δ SBP in European Americans (p value = 0.096), Hispanic/Latinos (p value = 0.069), African Americans (p value = 0.060), and in the whole cohort (p value = 0.083).