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. PRS were calculated for 1,027 bevacizumab-treated cancer patients of European descent from four clinical trials (Alliance/CALGB 80303, 40503, 90401, 40502) using summary systolic (SBP) and diastolic (DBP) genome-wide association results obtained from 757,601 European descent individuals. The association between PRS and grade 3 bevacizumab-induced hypertension (CTCAE v3) in each trial was performed by multivariable logistic regression. Fixed-effect meta-analyses odds ratios (OR) per standard deviation (SD) of the association of PRS (quantitative) and hypertension across trials were estimated by inverse-variance weighting. PRS were additionally stratified into quintiles, with the bottom quintile as the referent group. OR of the association between hypertension and each quintile versus the referent group was determined by logistic regression. The most significant PRS (quantitative)-hypertension association included up to 67 SNPs associated with SBP (p=0.0077, OR per SD=1.31, 95% 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 to 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.
【저자키워드】 hypertension, polygenic risk score, blood pressure, bevacizumab,