Polygenic Risk Scores for Blood Pressure to Assess the Risk of Severe Bevacizumab‐Induced Hypertension in Cancer Patients (Alliance)

Abstract

Hypertension is a common bevacizumab-induced toxicity. No markers are available to predict patients at risk of developing hypertension. We hypothesized that genetic risk of essential hypertension, as measured by a blood pressure polygenic risk score (PRS), would be associated with risk of severe bevacizumab-induced hypertension. PRSs were calculated for 1,027 bevacizumab-treated patients of European descent with cancer from four clinical trials (Alliance for Clinical Trials in Oncology (Alliance) / Cancer and Leukemia Group B (CALGB) 80303, 40503, 90401, 40502) using summary systolic blood pressure (SBP) and diastolic blood pressure (DBP) genome-wide association results obtained from 757,601 individuals of European descent. The association between PRS and grade 3 bevacizumab-induced hypertension (Common Toxicity Criteria for Adverse Events version 3) in each trial was performed by multivariable logistic regression. Fixed-effect meta-analyses odds ratios (ORs) per standard deviation (SD) of the association of PRS (quantitative) and hypertension across trials were estimated by inverse-variance weighting. PRSs were additionally stratified into quintiles, with the bottom quintile as the referent group. The OR of the association between hypertension and each quintile vs. the referent group was determined by logistic regression. The most significant PRS (quantitative)hypertension association included up to 67 single-nucleotide variants (SNPs) associated with SBP (P = 0.0077, OR per SD = 1.31, 95% confidence interval (CI), 1.07-1.60), and up to 53 SNPs associated with DBP (P = 0.0209, OR per SD = 1.27, 95% CI, 1.04-1.56). Patients in the top quintile had a higher risk of developing bevacizumab-induced hypertension compared with patients in the bottom quintile using SNPs associated with SBP (P = 4.75 × 10 −4 , OR = 3.72, 95% CI, 1.84-8.16) and DBP (P = 0.076, OR = 1.83, 95% CI, 0.95-3.64). Genetic variants associated with essential hypertension, mainly SBP, increase the risk of severe bevacizumab-induced hypertension.

Combating Hypertension Beyond GWAS: Microbiome and Artificial Intelligence as Opportunities for Precision Medicine

“…Previously, a PRS constructed utilizing genome-wide important single nucleotide polymorphisms from GWAS for BP showed a significant relationship with heart failure, left ventricular mass, coronary artery disease and stroke (Studies, 2011 ; Ference et al, 2014 ). Currently, there is considerable excitement in the field for developing reliable PRS for HTN as evident from multiple reports of PRS indices from different cohorts (Steinthorsdottir et al, 2020 ; Sapkota et al, 2021 ; Sato et al, 2021 ; Fujii et al, 2022 ; Parcha et al, 2022 ; Quintanilha et al, 2022 ). Recently, Weng et al ( 2022 ) included 391,366 participants from the UK Biobank database and established a PRS for HTN assessing the combined effect of genetic susceptibility and air pollution on incident of HTN.…”

Angiogenesis in Aortic Aneurysm and Dissection: A Literature Review

“…Currently, the anti-VEGF-A monoclonal antibody, bevacizumab, is approved as an effective adjunctive therapy for solid tumors [ 92 ]. However, severe hypertension is a common adverse effect of bevacizumab [ 93 ]. Regardless of whether Flt-1 or bevacizumab is used, local rather than systemic medical treatment may be more suitable for future clinical trials.…”

Combining pharmacogenetics and patient characteristic polygenic scores to improve outcome prediction for Calcium Channel Blocker treatment

“…exceptionally high genetic risks for CHD 22 . In addition to individual prediction, polygenic scores have been used to model the effects of risk traits, including BMI 23 for hypertension and CHD, and systolic and diastolic blood pressure genetic risk for phenotypic hypertension or diagnose cardiovascular diseases 24,25,26 . A recent UK Biobank study examining BP and low-density lipoprotein polygenic scores found that, among those treated for hypertension, an increased SBP polygenic score was still associated with uncontrolled hypertension 27 .…”