Balkan Journal of Medical Genetics

DETERMINATION OF THE RELATIONSHIP BETWEEN DNA METHYLATION STATUS OF KLOTHO AND ARNTL GENES WITH HYPERTENSION
Osum M, Tosun O, Birtan H, Kalkan R
*Corresponding Author: Prof. Dr.Rasime Kalkan, PhD, Faculty of Medicine, European University of Lefke, Mersin 10, Lefke 99728, Northern Cyprus, Turkey, kalkanr@yahoo.com, rkalkan@eul.edu.tr
page: 41

INTRODUCTION

Hypertension (HTN) is a common chronic disease in advanced age and is considered to influence 29% of adult individuals worldwide by 2025 [1]. HTN is one of the leading causes of kidney disease and cardiovascular complications, including stroke, coronary artery disease, heart failure, and peripheral vascular disease [2]. Gener- ally, HTN can be categorized into two groups, as primary (essential or idiopathic) and secondary (non-essential) hypertension. Approximately 90-95% of hypertensive cases have primary hypertension, 5-10% of hypertensive cases have secondary hypertension. Primary hyperten- sion is not due to other diseases and is affected by genetic and lifestyle factors. However, secondary hypertension is developed from kidney diseases, endocrine disorders, or side effects of drugs [3]. Mechanisms involved in the development of primary hypertension have been reported to be still unclear [1]. Numerous factors, including genetic, epigenetic, advanced age, smoking, overweight, diabetes, arterial aging, endothelial dysfunction, and arteriosclerosis contribute to HTN [4,5]. The heritability for HTN was indicated to be 30-60% [6]. KLOTHO (KL) was discovered as an aging suppres- sor gene encoding α-KL protein due to the determination of short lifespan and various aging-related phenotypes resembling human aging. These phenotypes include vas- cular calcification, atherosclerosis, cardiovascular disease in KL-deficient mice [7]. The KL gene is highly conserved in mice, rats and humans [8,9], and mainly expressed in the distal convoluted and proximal tubules of the kidney, choroid plexus of the brain and also other tissues such as the parathyroid glands, sinoatrial node, vascular tissue, car- tilage and bones [10]. More than 10 SNPs in the human KL gene have been reported [11,12]. KL gene polymorphisms such as G-395A [5,13], C1818T [2], and F352V [14] were associated with hypertension. The KL gene expression was shown to be lower in essential hypertensive patients in the Indian population [3]. Furthermore, a decrease in KL levels has been found in renovascular hypertensive patients. Thus, these results shed light on how the KL gene plays a crucial role in the pathophysiology of primary and secondary hypertension. Additionally, according to these results, it was suggested that KL could be utilized as a biomarker for the determination of kidney injury in hypertensive patients [1,15]. The circadian clock is a highly conserved system and provides adaptations of organisms to the environment cues along the 24-hour light/dark cycle [16]. It regulates most physiological processes, such as sleep-wake cycles, immune response, metabolism, renal function, and blood pressure [17]. The circadian clock is involved in the main- tenance of vascular function. It has been suggested that impaired clock function can lead to health complications such as cardiovascular disease and hypertension by con- tributing to vascular dysfunction [16, 18]. Aryl hydrocar- bon receptor nuclear translocator-like protein 1 (ARNTL or brain and muscle ARNT-like 1 (BMAL1)) is a core clock component and regulates the rhythmic expression of many genes as a transcription factor [19]. The ARNTL rs9633835 and rs6486121 polymorphisms were associated with sus- ceptibility to hypertension [20,21]. There have been studies investigating the connec- tion between the KL and ARNTL genes and hypertension through polymorphism and expression analyses, there is no published study that explores the correlation between the methylation status of these genes and hypertension, as well as the associated biochemical variables in both hyper- tensive and control subjects. Methylation is an epigenetic modification process that alters gene expression without changing the nucleotide sequence, thus contributing to the regulation of gene expression and maintenance of ge- nomic stability[22]. In this study, therefore, the methyla- tion status of the KL and ARNTL genes was analyzed in both hypertensive and control subjects. Furthermore, the possible effect of KL and ARNTL gene methylation on biochemical variables was analyzed in hypertensive and control subjects.

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