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

DISCUSSION

Hypertension is an important risk factor for kidney disease and cardiovascular diseases such as stroke, heart failure (HF) and arrhythmias [1,2]. The risk of hyper- tension significantly increases with age in both men and women [25]. However, the risk of hypertension exhibits variation based on gender. Particularly, the incidence of hypertension was found to be higher in postmenopausal women than those age-matched men and premenopausal women. It was suggested that obesity-mediated sympathet- ic activity, low estrogen level, and high renin-angiotensin system (RAS) activity might contribute to postmenopausal hypertension [26]. Human KL protein exists as a full-length single-pass transmembrane protein and soluble KL The soluble KL protein can be found in blood, urine, and cerebrospinal fluid [8,9]. A large proportion of soluble KL is provided from the kidney [7]. KL suppresses oxidative stress and aldosterone secretion, inhibits insulin/IGF-1 (insulin-like growth factor 1) and Wnt (wingless-related integration site) pathways, apoptosis, fibrosis and cell senescence, and regulates calcium-phosphate homeostasis [1]. KL-deficient mice were indicated to display aging-re- lated phenotypes, including hypertension, arterial stiffness, and chronic kidney disease (CKD) [27]. The silencing of KL gene was found to be related to hypertension and high level of aldosterone in human adrenocortical cells [28]. It was indicated that membranous and soluble KL can inhibit Wnt/β-mediated activation of RAS by blocking the bind- ing of Wnt ligands, and thus preserving kidney function and normalizing BP. Therefore, it was suggested that KL has an ameliatory effect on hypertension in CKD patients [29]. The soluble KL levels were found to be positively correlated with high-density lipoprotein-cholesterol (HDL-C) and negatively correlated with serum triglycerides in controls, and inversely correlated with body mass index (BMI) in hypertensive patients [3]. It was suggested that low plasma KL levels could increase total body sodium in patients, leading to chronic inflammation and high blood pressure. In addition, it was indicated that this process could be related to CKD patients with low serum KL levels [7]. It was reported that women with low serum KL con- centration have a high risk of postmenopausal hyperten- sion. It was suggested that serum KL concentration may be a significant biomarker to evaluate the risk of hyper- tension in postmenopausal women [26]. Several studies reported that the lower KL concentration was related to higher blood pressure, increasing the risk of hypertension [30,31]. In contrast, serum KL levels were detected not to be significantly different between subjects with and with- out hypertension in the general Chinese population [27]. Furthermore, a larger population-based study indicated no association between serum KL concentration and blood pressure [32,33]. In our study, we found no statistically significant link between KL methylation and hypertension (P>0.05). The difference between the studies’ findings could be the result of a limited sample size or the age of the population. Since changes in KL expression have been reported during aging, focusing on large-scale studies that evaluate the association between KL concentration, KL methylation, and hypertension in age-matched patients with different disease conditions and control subjects would be important. The soluble KL protein is produced by the kidney. Therefore, it is claimed that, in cases where the kidneys are normally functional and soluble KL pro- tein is at normal levels, KL expression may vary in other tissues. Thus, it is suggested that KL expression in other tissues may decline due to different factors, including ge- netic variants and epigenetic alteration [34]. Therefore, this information highlights how this situation should be taken into consideration in further studies. Particularly, it is defended that the effect of genetic polymorphisms in the KL gene on blood pressure should not be ignored [27]. Individuals with the GA+AA genotype of KL G-395A polymorphism were found to have a lower SBP, relative to the individuals with the GG genotype [35]. Thus, it was suggested that the A variant of KL G-395A might prevent the development of essential hypertension by increasing the KL levels [5, 13]. The uncertain mecha- nism affecting the human KL promoter region was indi- cated to inhibit KL gene expression in HEK293 cells [36]. The KL promoter region has been reported to be sensitive to DNA methylation [37, 38]. The KL-VS variant contains six variants, and two variants thereof are located in exon 2 cause amino acid substitutions, F352V and C370S. The KL-VS variant has been associated with enhanced SBP, serum cholesterol and cardiovascular disease in Baltimore Caucasian and African American subjects [39-41]. A meta- analysis has indicated that the G-395A, C1818T SNPs of the KL gene might be associated with a hypertension risk [2]. The F352V (rs9536314 T> G) polymorphism of the KL gene was correlated with salt-sensitive hypertension in an Italian study [14]. The KL rs9536314 and rs564481 polymorphisms were associated with increasing levels of HDL-C in females [42]. High HDL-C levels were sug- gested to be protective against KL dysfunction [40]. Par- ticularly, HDL and KL have been indicated to participate in the regulation of similar signaling pathways, including both molecules that promote nitric oxide (NO) synthesis, angiogenesis, and inhibit apoptosis, and insulin signaling in cell culture models [42, 43]. The fasting glucose was found to be predominantly higher in women with the T allele of KL rs564481 relative to non-carriers in Japanese [12] and Korean women [11]. It was reported that KL reduces the levels of serum creatinine. The decrease in KL expression has been related to aging-related kidney dam- age. Particularly, enhance in serum creatinine was indi- cated to be a diagnostic factor of acute kidney injury (AKI) [29]. Although several studies have reported a relationship between some biochemical parameters and KL protein, in our study, the relationship between the methylation status of KL and fasting glucose, triglyceride, total cholesterol, HDL-C, LDL-C, Na, K, Cr and Urea levels, were not sig- nificant (p > 0.05). It is considered that these contradictory results may be due to different genetic backgrounds in dif- ferent populations. However, levels of K were significantly different between the methylated KL hypertensive patients and unmethylated KL control subjects (p= 0,0014). The circadian clock regulates the circadian oscilla- tion of human blood flow by enhancing it during the day and decreasing it during the night [44]. Circadian clock genes were implicated in modulating many processes in- volved in the regulation of the blood pressure in the kidney, heart, vasculature, and metabolic organs [17]. It has been reported that the circadian oscillation of blood pressure decreases with age [45]. The global ARNTL knockout (KO) mice were found to have lower BP with impaired BP rhythm. It was shown that decreased BP can be associated with changes in the vasculature in ARNTL KO mice [18]. Furthermore, the global ARNTL KO mice were indicated to lose diurnal sodium excretion [46]. Smooth muscle components of the blood vessel wall provide sufficient blood flow to organs and blood pressure homeostasis by regulating its contrac- tile state. Smooth muscle-specific ARNTL KO male mice were shown to exhibit decreased BP and less impaired BP rhythm [16]. ARNTL rs3816358 polymorphism has been related to non-dipper hypertension in young hypertensive patients [47]. In rats, the ARNTL gene was stated to be situated in hypertension susceptibility loci. The 18477- T/G variant in the ARNTL promotor was reported to sig- nificantly decrease the Gata-4-mediated transcriptional activation of the ARNTL promotor. Moreover, in respect of this polymorphism, ARNTL promoter activity was in- dicated to be consistently 2-fold higher in normotensive Wistar-Kyoto (WKY) rats than in spontaneously hyper- tensive rats (SHR) [21]. It is suggested that hypertensive patients with the GG genotype of ARNTL A1420G may exhibit high nighttime SBP [48]. The essential arterial hypertension (EAH) patients with GG genotype of the circadian locomotor output cycles protein kaput (CLOCK) 257TG polymorphism were found to exhibit lower ARNTL expression than EAH patients with other genotypes at 9.00, 13:00, and 17:00 time points [49]. The downregulation of ARNTL levels was detected in hypertensive female patients [4]. Therefore, all these findings support that ARNTL is an essential factor during the development of hyperten- sion. However, the mechanisms underlying ‘’circadian genes’’ in the regulation of blood pressure have not been comprehended yet. According to our study, the ARNTL gene was methylated in 68.7% of the hypertensive sub- jects and the relationship between methylation status and hypertension was not significant (p > 0.05). Furthermore, the relationship between the methylation status of ARNTL and fasting glucose, triglyceride, total cholesterol, HDL-C, LDL-C, Na, K, Cr and Urea levels, were found to not be significant (p>0.05). In summary, we did not identify a statistically signifi- cant association between KLOTHO and ARNTL methyla- tion status and hypertension and their association with fasting blood sugar, triglycerides, total cholesterol, LDL- cholesterol, HDL-cholesterol, Na, K, Cr, Urea levels in hypertensive patients. The limitations of our study are the age mismatch between patients and controls, and the small number of participants. Since several factors such as age, gender and obesity and diabetes are risk factors for hy- pertension, patients and controls matched by age, gender, and BMI should be included in future studies to minimize the impact of these factors on the results [3]. Therefore, as mentioned in this study, these conditions should not be ignored in future large population-based studies.

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