Gene–Gene Interactions Among PRKCA, NOS3 and BDKRB2 Polymorphisms Affect the Antihypertensive Effects of Enalapril

Abstract

Protein kinase C (PKC) signalling is critically involved in the control of blood pressure. Angiotensin-converting enzyme inhibitors (ACEi) affect PKC expression and activity, which are partially associated with the responses to ACEi. We examined whether PRKCA (protein kinase C, alpha) polymorphisms (rs887797 C>T, rs1010544 T>C and rs16960228 G>A), or haplotypes, and gene-gene interactions within the ACEi pathway affect the antihypertensive responses in 104 hypertensive patients treated with enalapril as monotherapy. Patients were classified as poor responders (PR) or good responders (GR) to enalapril if their changes in mean arterial pressure were lower or higher than the median value, respectively. Multi-factor dimensionality reduction was used to characterize interactions among PRKCA, NOS3 (nitric oxide synthase 3) and BDKRB2 (bradykinin receptor B2) polymorphisms. The TC+CC genotypes for the rs1010544 polymorphism were more frequent in GR than in PR (p = 0.037). Conversely, the GA+AA genotypes for the rs16960228 polymorphism, and the CTA haplotype, were more frequent in PR than in GR (p = 0.040 and p = 0.008, respectively). Moreover, the GG genotype for the PRKCA rs16960228 polymorphism was associated with PR or GR depending on the genotypes for the rs2070744 (NOS3) and rs1799722 (BDKRB2) polymorphisms (p = 0.012). Our results suggest that PRKCA polymorphisms and gene-gene interactions within the ACEi pathway affect the antihypertensive responses to enalapril.

Pharmacogenetic implications in the management of metabolic diseases in Brazilian populations

“…Moreover, -58CC genotype was associated with better response depending on presence of NOS3 -786TC genotype (Silva et al, 2013). On the other hand, no association was found between BDKRB2, -58C>T and the response to enalapril in another sample of Brazilian HP subjects (Oliveira-Paula et al, 2017). The Indel BE1 9-bp repeat sequence was also not associated with the response to antihypertensive therapy in HP subjects (Silva et al, 2013;Oliveira-Paula et al, 2017).…”

“…Likewise, the NOS3 rs3918226T allele and TCA haplotype of the tagSNPs (rs3918188, rs3918226 and rs743506) were associated with better response, whereas the rs3918188A allele and CAG haplotype were associated with worse antihypertensive response to enalapril 10 and/ or 20mg/day (Oliveira-Paula et al, 2016). The NOS3 Asp298Glu (rs1799983) and 4b/4a VNTR polymorphisms were not associated with responsiveness to therapy (Silva et al, 2013;Oliveira-Paula et al, 2017) or with resistance to treatment (Sandrim et al, 2006;Yugar-Toledo et al, 2011) in Brazilian individuals.…”

“…The pharmacogenetic approaches in Brazilian population have involved primary (majority) hypertensive patients (HP), resistant hypertensive patients (RHP), gestational hypertensive (GHP) and preeclamptic patients (PP). The studies including GHP and PP were recently and very well reviewed by Luizon et al (2017). The main results of the pharmacogenetic studies with HP and RHP are described in this review.…”

“…PRKCA g.393521 (rs1010544) C allele was associated with better response to enalapril therapy, whereas the rs16960228 A allele and CTA haplotype had the opposite effect. Moreover, the rs16960228 GG genotype combined with BDKRB2 -58CC (rs1799722) and NOS3 -786TC or TT (rs2070744) genotypes were associated with good or poor response to treatment, respectively (Oliveira-Paula et al, 2017).…”

“…NOS3 variants have been the most studied in pharmacogenetic approaches with Brazilian hypertensive patients. The -786T>C (rs2070744) polymorphism was not associated with resistance to antihypertensive therapy (Sandrim et al, 2006), but it seems to be related to a better therapeutic response to enalapril (Silva et al, 2013;Oliveira-Paula et al, 2017). Likewise, the NOS3 rs3918226T allele and TCA haplotype of the tagSNPs (rs3918188, rs3918226 and rs743506) were associated with better response, whereas the rs3918188A allele and CAG haplotype were associated with worse antihypertensive response to enalapril 10 and/ or 20mg/day (Oliveira-Paula et al, 2016).…”