The epistasis between vascular homeostasis genes is apparent in essential hypertension
Introduction
Essential hypertension (EH) is a multigenic disease contributing to two-thirds of the cerebrovascular disease burden [1], [2]. It affects one billion people worldwide with increasing incidence; moreover, subjects with prehypertension are at a higher risk for cardiovascular diseases [3], [4]. The literature is replete with candidate gene studies; however, lack of substantial conclusion as well as conflicting and unsuccessful replication of results compels one to think beyond individual genes and individual polymorphisms in adjudicating multifactorial diseases. The possible reason could be attributed to lack of investigations on epistasis that may provide a robust nexus among various pathophysiological pathways involved in diseased- and normal-state. Moreover, revelation of the significance of epistasis on heart rate variability, hypertension, lung cancer and asthma [5], [6], [7], [8], [9], further support our hypothesis of exploring the epistasis of blood pressure (BP) regulation pathways.
The renin-angiotensin-aldosterone system (RAAS) and Kallikrein-kinin system (KKS) are the two proteolytic cascades that counteract to regulate BP and electrolytes. The key role of the gene products and inhibitors of these pathways in the regulation of BP strongly motivates the study of the respective genes [10], [11], particularly their interactions in human hypertension. The cross-talk of genes, such as angiotensin-1 converting enzyme (ACE) and aldosterone synthase (CYP11B2) of RAAS and endothelial nitric oxide synthase (NOS3) of KKS would surely influence the physiological functions; however, the genetic variants may bring in inconsistency in the physiological functions. To test our hypothesis in a case-control design, we (i) determined systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), ACE activity, NOx (nitrite + nitrate) level, plasma aldosterone concentration (PAC), (ii) screened seven single nucleotide polymorphisms (SNPs) of ACE, CYP11B2 and NOS3, (iii) looked for the plausible interactions between and among these SNPs through pairwise genotypes interaction and haplotypes interaction and finally, (iv) correlated these interactions with clinical and biochemical parameters in age- and ethnicity-matched subjects.
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Study participants and clinical evaluation
The study was approved by human ethical committee; written informed consent was obtained from each participant. More than 2500 unrelated, consecutive north-Indian participants were screened through the hypertension outpatient clinic of the GB Pant hospital, New Delhi. Among these a significant number of subjects could not be included because either they did not consent, were already on medication or due to various other restrictive factors, therefore we were left with 860 case-control
Demographic, clinical and biochemical characteristics
The main characteristics of the participants are presented in Table 1. The clinical parameters such as SBP, DBP and MAP were significantly higher in patients than controls (P < 0.0001, each); likewise the biochemical parameters such as ACE activity and PAC were higher, whereas NOx level was significantly lower in patients than controls (P < 0.0001, each).
Gene–gene interactions and the hypertension risk
The allele and genotype frequencies were in HWE (P > 0.05) except for the NOS3 894G/T polymorphism (P = 0.001) in patients. The −344T/C of CYP11B2 was
Discussion
Our investigation of the three most important genes of vascular homeostasis pathway revealed epistatic interactions between CYP11B2 and NOS3. The interacted-genotypes IcIc + 4aa showed higher odds ratio compared to individual risk genotypes, IcIc of CYP11B2 and 4aa of NOS3. Similarly, the two interacted-haplotypes, IHT1 (−344T/Ic) + (−922A/−786T/4a/894G) and IHT2 (−344T/Ic) + (−922G/−786C/4a/894G) of CYP11B2 and NOS3 also showed higher odds ratio compared to individual risk haplotypes. Among the
Source of funding
The Council of Scientific and Industrial Research, India supported this work financially.
Disclosures
No conflicts of interest declared.
Acknowledgements
We highly appreciate the support and constant encouragement of Director, Institute of Genomics and Integrative Biology as well as the staff at the Department of Cardiology, GB Pant Hospital, New Delhi.
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