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(TRPM) Channel Gene Polymorphisms in Obesity-Related Metabolic Syndrome

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(TRPM) Channel Gene Polymorphisms in Obesity-Related Metabolic Syndrome Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2015; 19: 1388-1397 Role of the transient receptor potential (TRP) channel gene expressions and TRP melastatin (TRPM) channel gene polymorphisms in obesity-related metabolic syndrome S. TABUR 1, S. OZTUZCU 2, I.V. DUZEN 3, A. ERAYDIN 1, S. EROGLU 2, M. OZKAYA 1, A.T. DEMIRYÜREK 4 1Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey 2Department of Medical Biology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey 3Department of Cardiology, 25 Aralık State Hospital, Gaziantep, Turkey 4Department of Medical Pharmacology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey Abstract. – OBJECTIVE: Metabolic syndrome This study also revealed that there is a signifi - (MetS) is correlated with increased cardiovascu - cant relationship between TRP channels gene lar risk and characterized by several factors, in - expressions and MetS. cluding visceral obesity, hypertension, dyslipi - demia, and insulin resistance. The etiology of Key Words: MetS is complex, and can be influenced by ge - Expression, Gene variants, Metabolic syndrome, netic susceptibility. The aim of this study was to Obesity, Transient receptor potential. investigate a possible association of transient receptor potential (TRP) channels gene expres - sions and TRP melastatin (TRPM) gene polymor - Introduction phisms with MetS in a Turkish population. PATIENTS AND METHODS: A total of 142 pa - Metabolic syndrome (MetS) is characterized tients with obesity-related MetS and 166 healthy controls with similar age and sex were enrolled by a combination of visceral obesity, hyperten - to this study. For polymorphism studies, genom - sion, insulin resistance, dyslipidemia, and im - ic DNA from the participants was analyzed by a paired glucose tolerance. Experimental, epidemi - BioMark 96.96 dynamic array system (Fluidigm, ological, and clinical studies have demonstrated South San Francisco, CA, USA). For gene ex - that patients with MetS have significantly elevat - pression studies, mRNA from blood samples ed cardiovascular morbidity and mortality 1. The was extracted, and real time polymerase chain 2 reaction on the BioMark HD system was per - prevalence of MetS is about 30% worldwide . formed. The prevalence of obesity and the MetS is rapid - RESULTS: There was an increase in A allele ly increasing, leading to increased morbidity and (64.6% in patients vs. 49.5% in controls) and de - mortality. A survey in Turkey reported a preva - crease in G allele frequencies (35.4% in patients lence of 33.9% for the MetS, with a higher vs. 50.5% in control, p = 0.0019) of the TRPM5 prevalence in women (39.6%) than in men gene rs4929982 (Arg578Gln) polymorphism. We (28%) 3. The prevalence of MetS was also found also observed that the distribution of genotype and allele frequencies of the TRPM8 gene to be 37.5% in Turkish patients with non-diabetic 4 rs12472151 in MetS patients were significantly first acute ST elevation myocardial infarction . different from controls ( p < 0.0001). Although The exact cause of MetS is not known. Several there were marked decreases in TRPC1, TRPC3, studies have found that people with higher calci - TRPM2, TRPM5, TRPV4, TRPV5, TRPV6, MCOLN2 um intakes have a lower prevalence of MetS and (TRPML2), and MCOLN3 (TRPML3) gene expres - its components 5-7 . Calcium is known to play a sions, an augmentation was noted in TRPC6 gene expression. key role in blood pressure control and adipocyte CONCLUSIONS : Genetic polymorphisms in metabolism, and thus its effects on MetS could TRPM5 and TRPM8 genes may modify individual be partially mediated by its effects on body fat, susceptibility to MetS in the Turkish population. blood pressure, and insulin sensitivity 8. 1388 Corresponding Author: Suzan Tabur, MD; e-mail: [email protected] TRP channels in metabolic syndrome Transient receptor potential (TRP) channels controls evaluated at Division of Endocrinology, are the recently discovered major ion channel su - Department of Internal Medicine, Faculty of perfamily. There are 28 mammalian TRP chan - Medicine, Gaziantep University, Gaziantep, nels, which are subdivided into six subfamilies Turkey were recruited into this study. The study based on protein sequence homology: TRPC for was approved by the local Ethics Committee, and “canonical” (TRPC1–7), TRPV for “vanilloid” written informed consent prior to participation in (TRPV1–6), TRPM for “melastatin” (TRPM1– the study was obtained from patients and healthy 8), TRPP for “polycystin” (TRPP2, TRPP3, volunteers according to the Declaration of TRPP5), TRPML for “mucolipin” (TRPML1–3), Helsinki. and TRPA for “ankyrin” (TRPA1) 9,10 . TRP chan - MetS was defined by using modified criteria nels are non-selective channels permeable to proposed by the Third Report of the National monovalent and divalent cations. Thus, changes Cholesterol Education Program Adult Treatment in the function or expression of TRP channels Panel 22,23 . A MetS diagnosis was made when a could alter intracellular Ca 2+ levels directly, indi - subject fulfilled three of the following five crite - rectly or through membrane potential and the ria: waist circumference 102 cm in men and 2+ 11 ≥ ≥ regulation of L-type Ca channel activity . 88 cm in women, triglyceride (TG) ≥ 150 mg/dl TRP channels are broadly distributed in sever - or treatment of dyslipidemia, high density al cell types, including adipocytes, vascular lipoprotein (HDL ) cholesterol < 40 mg/dl in men smooth muscle cells and endothelial cells, which and < 50 mg/dl in women or treatment of dyslipi - explains their wide spread function. Thus demia, systolic and diastolic blood pressure ≥ changes in expression or disturbance of TRP 130 and 85 mm Hg or antihypertensive treat - channel function likely result in the development ment, and fasting blood glucose ≥ 100 mg/dl or of MetS. Oxidative stress is known to play a ma - treatment of type 2 diabetes. Patients who had a jor role in the pathogenesis of MetS 12-14 . TRPM history of percutaneous coronary intervention channels are also activated by oxidative stress 10 . within 6 months or coronary artery bypass Our hypothesis is that the TRPM polymorphisms surgery within 1 year were excluded. Other ex - or gene expressions are associated with MetS. clusion criteria included patients who had heart The progression of MetS is influenced by genetic failure, cardiomyopathy, or valvular heart dis - susceptibility and environmental factors, including eases. All patients were in the follow up of the diet, and the interactions between them 15-17 . Heri - Endocrinology Clinic. tability estimates of the MetS range from 13% to All sex and age-matched controls were healthy 27% 18,19 . Recently, published genome-wide associa - and had no symptoms of MetS. The selection cri - tion studies have described candidate genes, includ - teria of the controls were that all control subjects ing fat mass and obesity associated ( FTO ) and were from the same geographical area with a melanocortin 4 receptor ( MC4R ) genes, that con - similar socioeconomic and ethnic background tribute to MetS and its phenotypes around the and were admitted to outpatient clinic. The so - world 20,21 . Changes of TRP channel gene expres - cioeconomic background was identified by the sions or polymorphisms may account for the ob - information obtained from the patient and the served increased cardiovascular risk in MetS pa - controls through a health questionnaire. All the tients. A finding of gene-calcium interactions could patients and controls were in the middle income improve our understanding of the mechanisms of status. Exclusion criteria for selecting control metabolic alterations and could eventually lead to subjects were presence of coronary artery dis - effective, personalized prevention of MetS. Thus, in ease, peripheral occlusive arterial disease, coagu - this study we aimed to investigate whether TRP lopathy, vasculitis, autoimmune disease, severe channel gene expressions and TRPM gene poly - kidney and hepatic diseases, cancer, and preg - morphisms are associated with susceptibility to nancy. obesity-related MetS in a Turkish population. Biochemical Analysis Venous blood samples were drawn from each Patients and Methods subject after ≥ 8 h or overnight fasting. The sam - ples were stored at –80°C until biochemical as - Study Populations say by blinded investigators. All routine chem - A total of 308 unrelated Turkish subjects, 14 2 istry was conducted by the standard laboratory with obesity-related MetS and 166 non-MetS techniques in the Clinical Biochemistry Labora - 1389 S. Tabur, S. Oztuzcu, I.V. Duzen, A. Eraydin, S. Eroglu, M. Ozkaya, A.T. Demiryürek tory. Triglycerides were determined enzymatical - PKD2 (TRPP2) ] for expression study. Data were ly. High-density lipoprotein cholesterol was mea - analyzed using the 2 -∆Ct method, according to the sured by the phosphotungstate method. Glucose formula: ∆Ct = C tTR – C tACTB , where C t = thresh - was enzymatically determined by the hexokinase old cycle. method. Statistical Analysis Blood Samples and DNA Isolation Results are expressed as the means ± S.D. or Peripheral venous blood samples (5 ml) were percentage otherwise indicated. The Chi-square collected by venipuncture into sterile siliconized test for independence, Chi-square test with Yate’s Vacutainer tubes with 2 mg/ml disodium ethyl - correction or Fisher’s exact tests were used for enediaminetetraacetic acid. All
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