Elsevier

Atherosclerosis

Volume 220, Issue 2, February 2012, Pages 418-424
Atherosclerosis

The epistasis between vascular homeostasis genes is apparent in essential hypertension

https://doi.org/10.1016/j.atherosclerosis.2011.10.036Get rights and content

Abstract

Objective

The epistasis influence of vascular homeostasis genes is vital to multigenetic diseases. This study was designed to perceive the possible role of epistasis in the etiology of essential hypertension.

Methods

We investigated seven polymorphisms of ACE, CYP11B2 and NOS3 epistatically, and SBP, DBP, MAP, ACE activity, plasma aldosterone concentration (PAC) and NOx level in 860 age- and ethnicity-matched unrelated north-Indian subjects.

Results

The hypertension risk in individuals with interacted-genotypes (IwIw + IwIc) + (4aa), (IcIc) + (4bb + 4ba) and IcIc + 4aa of the CYP11B2 and NOS3 was significantly higher with odds ratio 5.5 (95% CI = 2.9–10.6, P < 0.0001), 2.4 (95% CI = 1.4–4.1, P < 0.0008) and 7.5 (95% CI = 1.6–34.8, P = 0.010), respectively. The odds ratio for hypertension with interacted-haplotypes (−344T/Ic) + (−922A/−786T/4a/894G) and (−344T/Ic) + (−922G/−786C/4a/894G) of CYP11B2 and NOS3 was 5.3 (95% CI = 2.0–14.2, P = 0.005) and 3.9 (95% CI = 1.4–10.4, P = 0.04), respectively; whereas for the protective interacted-haplotypes (−344T/Iw) + (−922A/−786T/4b/894G), the odds ratio was 0.7 (95% CI = 0.5–0.9, P = 0.03). While the interacted-genotypes, IcIc + 4aa correlated with higher SBP and MAP (P = 0.006; P = 0.04), the interacted-haplotypes, (−344T/Ic) + (−922A/−786T/4a/894G) and (−344T/Ic) + (−922G/−786C/4a/894G) correlated with higher MAP and lower NOx level (P = 0.02 and P = 0.03, respectively), and the protective interacted-haplotypes (−344T/Iw) + (−922A/−786T/4b/894G) correlated with lower PAC and MAP (P = 0.024 and P = 0.018, respectively).

Conclusions

The epistasis between CYP11B2 and NOS3 and its correlation with varied clinical and biochemical parameters signify its possible contribution in the complex etiology of 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.

Section snippets

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.

References (30)

  • J.A. Whitworth

    World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension

    J Hypertens

    (2003)
  • R.S. Vasan et al.

    Impact of high-normal blood pressure on the risk of cardiovascular disease

    N Engl J Med

    (2001)
  • N. Hizawa et al.

    Genetic polymorphisms at FCER1B and PAI-1 and asthma susceptibility

    Clin Exp Allergy

    (2006)
  • M. Misono et al.

    Combination of polymorphisms in the beta2-adrenergic receptor and nitric oxide synthase 3 genes increases the risk for hypertension

    J Hypertens

    (2009)
  • P.P. Laurila et al.

    Genetic association and interaction analysis of USF1 and APOA5 on lipid levels and atherosclerosis

    Arterioscler Thromb Vasc Biol

    (2010)
  • Cited by (9)

    View all citing articles on Scopus
    View full text