Multi-locus interactions of vascular homeostasis genes in essential hypertension: A gender-based study

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Abstract

Background

Studies on genes of endothelial and vascular homeostasis are inadequate in females.

Methods

We investigated the role of 7 variants of ACE, AGT and NOS3 and their correlation with NOx levels and ACE activity in hypertension susceptibility in 910 case–controls of both genders.

Results

Prevalence of alleles D of ACE I/D; − 6A of AGT 6G/A; − 786C, 894T and 4a of NOS3 786T/C, 894G/T and 4b/4a polymorphisms was observed in patients (P  0.05). The 3 genotypes-combinations containing 6 + 5 wild-type alleles of AGT and NOS3 were significantly less prevalent in patients (P  0.0003). The haplotypes 235T/174T/− 6A of AGT (P = 4E− 3) and − 786T/894G/4a and − 786C/894G/4a of NOS3 (P = 2E− 3, P = 0.011, respectively) were significantly more prevalent in patients. The AGT and NOS3 findings were similar in males. Genotypes-combinations with 6 + 5 wild-type alleles of AGT correlated with higher NOx levels (P = 0.03). The NOS3 genotypes-combinations having 6 and 6 + 5 wild-type alleles correlated with decreased ACE activity (P = 0.025, P = 0.0015, respectively) and increased NOx levels (P = 0.001, P = 0.0001, respectively) in patients. In gene–gene interactions, ACE D allele associated with ≤ 4 wild-type alleles containing genotypes-combinations of AGT and NOS3 in patients (P  0.04).

Conclusion

Within gene and between genes interactions of variants influence ACE activity and NOx levels and associate with EH.

Introduction

Essential hypertension (EH) affects one billion people worldwide with increasing incidence, yet the underlying pathogenetic pathways remain largely elusive [1], [2]. The ever changing lifestyle has caused substantial increase in hypertension in the Indian subcontinent; almost equal percentage of Indians, male or female, is reported having hypertension [3], although some rural to urban variations are present [4]. Literature is dominant with male findings, although, hypertension is understandably important in females because it is a modifiable risk factor that is extremely prevalent in older women [5]. Gene by gender interaction reveals the gender specific effects of the single nucleotide polymorphisms, haplotypes and gene by gene (epistatic) interaction on blood pressure in males and females [6]. The renin–angiotensin–aldosterone system (RAAS) and Kallikrein–Kinin System (KKS) are the two proteolytic cascades that influence blood pressure regulation and electrolyte homeostasis. It is strongly believed that alterations of genes involved in endothelial and vascular homeostasis play a causative role in EH pathogensis [7], [8], [9], [10], [11], [12], [13].

Relationship between genotype and phenotype is expected to be nonlinear in cardiovascular diseases suggesting that the underlying genetic basis in blood pressure is not on the basis of individual genes, but certainly an interaction among multiple loci [14], [15], [16]. Therefore, a single genetic variant due to its modest effect may not be influential. Whereas, candidate genes may act epistatically in the etiology of the disease [17], [18], [19]. The genetic association studies have been often investigated in EH in different ethnic population, however, similar reports especially on female cohorts are strikingly limited. To address these issues, 7 genetic variants were selected from angiotensin-I converting enzyme (ACE), angiotensinogen (AGT) and endothelial nitric oxide synthase (NOS3) to perform an association study in well-characterized gender-based cohorts with case–control design. The emphasis has been on gender-based comparisons so as to elucidate the extent of uniformity and deviations. The objective being, to investigate the polymorphisms individually, in combination and as haplotypes, and their correlations with related phenotypes for association with EH; to understand the extent of involvement of each allele in the interacting mode, if any, so as to bring forth the effectiveness of the genotypes-combinations, both within gene and between genes (epistasis) and haplotypes.

Section snippets

Study subjects and clinical evaluation

The study was approved by the ethical review committee and each subject read and signed the informed consent form. The total North Indian ethnically matched unrelated consecutive participants screened were 2360. A significant number of subjects could not be included because either they did not consent, were already on medication or the various other limiting factors (majority of them females), hence we were left with 910 case–control participants of both gender of which 350 were females

Demographic characteristics and biochemical status

The main clinical, demographic and biochemical characteristics of both genders are presented in Table 1. BMI, SBP, DBP, pulse rate, triglyceride and total cholesterol levels varied significantly within the two genders; the males had higher values. NOx level was significantly decreased, whereas, ACE activity was increased in patients than controls (P < 0.0001, each). To avoid perplexity, the rest of the findings has been described individually for both genders.

Single-locus association analyses

We looked for tagging efficiency of

Discussion

The distribution of few alleles of the polymorphisms significantly associated with EH in our study population and the associations suggested that both genders followed a similar trend. The allelic presentations of the individual polymorphisms as obtained through the dominant model revealed prevalence of the minor alleles D of ACE, 235T and − 6A, of AGT and − 786C, 894T and 4a of NOS3 in patients. Another of our observation on ACE I/D is that the I allele frequency in females is comparatively

Acknowledgements

The Council of Scientific and Industrial Research, India supported this work financially. We highly appreciate Director, Institute of Genomics and Integrative Biology for his support and constant encouragement.

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