PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors

Abstract

No biomarkers are available to predict patients at risk of developing hypertension induced by VEGF-pathway inhibitors. This study aimed to identify predictive biomarkers of hypertension induced by these drugs using a discovery-replication approach. The discovery set included 140 sorafenib-treated patients (TARGET study) genotyped for 973 SNPs in 56 genes. The most statistically significant SNPs associated with grade ≥2 hypertension were tested for association with grade ≥2 hypertension in the replication set of a GWAS of 1039 bevacizumab-treated patients from four clinical trials (CALGB/Alliance). In the discovery set, rs444904 (G > A) in PIK3R5 was associated with an increased risk of sorafenib-induced hypertension (p = 0.006, OR = 3.88 95% CI 1.54-9.81). In the replication set, rs427554 (G > A) in PIK3R5 (in complete linkage disequilibrium with rs444904) was associated with an increased risk of bevacizumab-induced hypertension (p = 0.008, OR = 1.39, 95% CI 1.09-1.78). This study identified a predictive marker of drug-induced hypertension that should be evaluated for other VEGF-pathway inhibitors.ClinicalTrials.gov Identifier:NCT00073307 (TARGET).

Figure 1.. CONSORT and quality control flowchart for the TARGET study.

IBS: identical by state, MAF: minor allele frequency, HWE: Hardy-Weinberg Equilibrium, QC: quality control, SNP: single nucleotide polymorphism.

Figure 2.. Effect of genotypes of rs427554 on bevacizumab-induced hypertension (replication set).

CALGB: Cancer and Leukemia Group B.

Figure 3.. Proposed model for lower and higher risk of developing hypertension induced by VEGF-pathway inhibitors in patients with the G and A allele of rs444904 and rs427554 (Created with BioRender.com.).

A: The G allele of rs444904 and rs427554 increases the binding of the SP1 transcription factor, which inhibits the action of DNMT, activating PIK3R5 transcription and leading to a higher activation of AKT/NO/mTOR signaling pathway. Higher activation of AKT/NO/mTOR leads to vasodilation and lower risk of developing hypertension. B: SP1 binds inefficiently to the A allele of rs444904 and rs427554, which allows DNA methylation by DNMT, repressing PIK3R5 transcription and leading to a lower activation of AKT/NO/mTOR signaling pathway. Lower activation of AKT/NO/mTOR leads to vasoconstriction and higher risk of developing hypertension. VEGF: Vascular endothelial growth factor, VEGFR2: VEGF receptor 2, GPCR: G-protein-coupled receptor, DNMT: DNA methyl transferase, PI3K: Phosphatidylinositol-3-kinase, PIP2/3 phosphatidylinositol 3,4,5-bi/triphosphate, NO: nitric oxide, NOS: NO synthase, mTOR: mammalian target of rapamycin.