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Genetic predisposition to bevacizumab-induced hypertension.
- Source :
-
Gynecologic oncology [Gynecol Oncol] 2017 Dec; Vol. 147 (3), pp. 621-625. Date of Electronic Publication: 2017 Sep 29. - Publication Year :
- 2017
-
Abstract
- Objective: Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH).<br />Methods: Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using mass spectrometry. Bevacizumab toxicities were identified from clinical trial reports. Haplotypes were reconstructed from diploid genotyping data and frequencies were compared using standard two-sided statistical tests.<br />Results: The study included 114 patients with breast, lung, ovarian, or other cancers, of whom 38 developed BIH. WNK1, KLKB1, and GRK4 were found to contain single loci associated with BIH. Haplotype analysis of WNK1, KLKB1, and GRK4 identified risk haplotypes in each gene associated with grade 3/4 BIH. A composite risk model was created based on these haplotypes. Patients with the highest risk score were the most likely to develop grade 3/4 BIH (OR=6.45; P=0.005; 95%CI, 1.86-22.39).<br />Conclusions: We concluded that genetic variation in WNK1, KLKB1, and GRK4 may be associated with BIH. These genes are biologically plausible mediators due to their role in blood pressure control, regulating sodium homeostasis and vascular tone. This preliminary risk model performed better than population-based risk models and when further validated may help risk-stratify patients for BIH prior to initiating therapy.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Immunological adverse effects
Case-Control Studies
Female
G-Protein-Coupled Receptor Kinase 4 genetics
Genetic Predisposition to Disease
Haplotypes
Humans
Kallikreins genetics
Male
Middle Aged
Neoplasms drug therapy
Polymorphism, Single Nucleotide
WNK Lysine-Deficient Protein Kinase 1 genetics
Bevacizumab adverse effects
Hypertension chemically induced
Hypertension genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1095-6859
- Volume :
- 147
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Gynecologic oncology
- Publication Type :
- Academic Journal
- Accession number :
- 28969913
- Full Text :
- https://doi.org/10.1016/j.ygyno.2017.09.017