Regeneron Genetics Center,

bioRxiv2019

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

BackgroundThe 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 1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery.\n\nMethodsWe 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).\n\nResults4,317 patients met inclusion criteria, of which 3,699 were genotyped. Average {Delta}BP 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}SBPEA=20(+-24) mmHg; {Delta}SBPHA=16(+-25) mmHg; {Delta}SBPAA=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.\n\nConclusionsIt 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.

genomics↗

bioRxiv2019

GSTM1 copy number is not associated with risk of kidney failure in a large cohort

Deletion of glutathione S-transferase {micro}1 (GSTM1) is common in populations and has been asserted to associate with chronic kidney disease progression in some research studies. The association needs to be validated. We estimated GSTM1 copy number using whole exome sequencing data in the DiscovEHR cohort. Kidney failure was defined as requiring dialysis or receiving kidney transplant using data from the electronic health record and linkage to the United States Renal Data System, or the most recent eGFR < 15 ml/min/1.73m2. In a cohort of 46,983 unrelated participants, 28.8% of blacks and 52.1% of whites had 0 copies of GSTM1. Over a mean of 9.2 years follow-up, 645 kidney failure events were observed in 46,187 white participants, and 28 in 796 black participants. No significant association was observed between GSTM1 copy number and kidney failure in Cox regression adjusting for age, sex, BMI, smoking status, genetic principal components, or co-morbid conditions (hypertension, diabetes, heart failure, coronary artery disease, and stroke), whether using a genotypic, dominant, or recessive model. In sensitivity analyses, GSTM1 copy number was not associated with kidney failure in participants that were 45 years or older at baseline, had baseline eGFR < 60 ml/min per 1.73 m2, or with baseline year between 1996-2002. In conclusion, we found no association between GSTM1 copy number and kidney failure in a large cohort study.\n\nTranslational StatementDeletion of GSTM1 has been shown to be associated with higher risk of kidney failure. However, inconsistent results have been reported. We used electronic health record and whole exome sequencing data of a large cohort from a single healthcare system to evaluate the association between GSTM1 copy number and risk of kidney failure. We found no significant association between GSTM1 copy number and risk of kidney failure overall, or in multiple sensitivity and subgroup analyses.

genetics↗