Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance)

Abstract

Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood. To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes. Four common variants in independent linkage disequilibrium blocks between and were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension ( = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg ( = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 ( = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure. The genomic region between and and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. .

Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors

“…Genetic variability of drug metabolism, transporters, or therapeutic targets may influence paclitaxel or sorafenib PK. Several genetic polymorphisms, including those affecting angiogenesis-related genes VEGFA, VEGFR-1, VEGFR-2, VEGFR-3, adenosine/endothelial nitric oxide synthase (eNOS) signaling (SLC29A1 and HSP90AB1), and immunomodulatory pathways have been previously correlated with safety and efficacy of anti-VEGF agents (37)(38)(39)(40)(41). We observed no correlations between genotypes tested and toxicity in this study.…”

<p>Pharmacogenomics and Pharmacogenetics: In Silico Prediction of Drug Effects in Treatments for Novel Coronavirus SARS-CoV2 Disease</p>

“… 1450044669 59 CTNNB1 Intergenic variant g.203866282A>G rs4553808 Patients with the AA who are treated with dexamethasone and prednisone may have a later onset of bortezomib-induced peripheral neuropathy as compared to patients with the AG or GG genotype. 1043880851 60 PNPLA3 c.432C>G rs738409 Patients with the CG genotype may have increased risk of hepatotoxicity when treated with remission induction therapy as compared to patients with genotype CC. 1448632697 61 Captopril ACE Intron variant c.584–105_584-104ins rs1799752 Patients with the ATACAGTCACTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC/del genotype and conditions such as heart failure, chronic obstructive pulmonary disease and Type 2 diabetes may have an increased response when treated with captopril as compared to patients with the del/del genotype, or a decreased response compared to patients with the ATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC/ATACAGTCACTTTTTTTTTTTTTTGGACACGGAGTCTCGCTCTGTCGCCC genotype.…”

Analysis of key genes and pathways associated with the pathogenesis of Type 2 diabetes mellitus

“…A previous study demonstrated that IGFBP5 [219], PRDX6 [220], PKM (pyruvate kinase M1/2) [221], PRDX1 [222] and USP22 [223] were more highly expressed in diabetic nephropathy, but these genes might be novel target for T2DM. Durgin et al [ [228], Lin et al [229] and Schweigert et al [230] suggested that CYB5R3, CACNA1A, GLCCI1, CAP1, HSP90AB1, BLVRA (biliverdinreductase A) and CRIP1 were involved in the progression of hypertension, but these genes might be novel target for T2DM.…”