Real-time Pharmacogenomics: Genetic Factors Impacting Phenylephrine Response During Surgery. J. M. Jeff1, T. Joesph2, K. Slivinski1, M. Yee3, A. Owusu Obeng1,4,5, S. B. Ellis1, E. P. Bottinger1, O. Gottesman1, M. A. Levin2,6, E. E. Kenny1,7,8,9 1) Charles F. Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, NY; 2) Department of Anesthesiology, Icahn School of medicine at Mount Sinai Hospital, New York; 3) Carnegie Institution for Science, Dept. of Plant Biology, Stanford, CA; 4) Division of General Internal Medicine, Icahn School of medicine at Mount Sinai Hospital, New York; 5) Department of Pharmacy, Icahn School of Medicine at Mount Sinai Hospital, New York; 6) Division of Cardiothoracic Anesthesia, Icahn School of Medicine at Mount Sinai Hospital, New York; 7) Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY; 8) Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY; 9) Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, NY.

   We present a novel pharmacogenomic approach in which we define real-time drug response to intravenous medication administered during surgery. We have built a database of surgical procedures that capture drug administration events and succeeding physiological responses, as well as type and length of surgery, anesthetic technique, quantity of fluids administered and other patient information. These data are linked to an internal Biobank of patients from New York, with genotype, sequence, and rich phenotypic data from the electronic medical record. Leveraging this resource, we investigated real-time response to phenylephrine, a selective 1-adrenergic receptor agonist that is used to treat hypotension during surgery. After extensive analyses of possible confounders, we excluded patients whose mean arterial pressure (MAP) before or after drug bolus was outside the normal MAP range (30-130mmHG), cases with poorly recorded physiological data, and those who received 5L fluids or blood products during surgery, resulting in 866 patients for genetic analyses. We found that administration of a bolus of phenylephrine (50-200g) increases MAP an average of 17.25 mmHg(SE1.29), 13.3 mmHg(SE1.01), and 15.21 mmHg(SE0.98), in self-reported European-Americans (EA;n=168), African-Americans (AA;n=208) and Hispanic/Latino (HL;n=292), respectively. Overall EAs have a greater response to phenylephrine compared to HLs and AAs (F=6.24;P0.008). We performed a GWAS with 1000 Genomes imputed genotypes to test whether genetic variation influences MAP after phenylephrine drug bolus. We confirmed associations in biologically relevant 1-adrenergic receptors, ADRA1A and ADRA1B (p10-3). Notably, we discovered a significant GWAS signal in EAs (rs2320937;chr2:134341287;P4.7E-8;=-0.71;MAF=0.26) that explains 18% of the variance in drug response and replicated in an independent cohort of EAs (n=50,rs62177704,chr2:134234306; P1.7E-4, =-1.49, MAF=0.07). Homozygous non-reference individuals have an attenuated drug response (2.43 mmHG,SE6.33) compared to non-carriers (25.75 mmHG,SE2.33). The signal resides upstream of NCK-associated protein 5 gene, NCKAP5, which is involved in the blood coagulation pathway via Factor Xa. This work demonstrates our ability to define real-time drug response, detect large effect alleles and novel genes affecting pharmaceutical response, and identify a subset of phenylephrine non-responders with implications for personalized treatment during surgery.

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