Hypomethylation of the Toll-like receptor-2 gene increases the risk of essential hypertension.

Studies on the etiology of essential hypertension (EH) have demonstrated that chronic inflammation contributes to the onset and development of elevated blood pressure. Toll‑like receptors (TLRs), important immune receptors, serve a role in chronic inflammation and are associated with EH. In the present study, 96 patients with EH, and 96 age‑ and sex‑matched healthy controls were recruited, and eight cytosine‑phosphate‑guanine (CpG) dinucleotides (CpG1‑8) were analyzed using bisulfite pyrosequencing technology. It was observed that the methylation levels of all of the eight CpG dinucleotides were decreased in the EH group compared with the control group; however, only CpG1 (2.83±1.34 vs. 3.44±1.75; P=0.009), CpG6 (3.58±3.64 vs. 8.30±4.13; P<0.001) and CpG8 (8.91±5.32 vs. 11.33±3.87; P<0.001) were significantly different, as demonstrated by paired t‑test analysis. In addition, logistic regression analysis demonstrated that CpG6 hypomethylation was a risk factor of EH (odds ratio=1.10; adjusted P=0.009), and CpG6 methylation level was observed to be negatively correlated with systolic blood pressure (r=‑0.304; P<0.001) and diastolic blood pressure (r=‑0.329; P<0.001). Additionally, receiver operating characteristic curve analysis demonstrated that a methylation level of 7.5% for CpG6 (area under the curve, 0.834; P<0.001) was an appropriate threshold value to predict the risk of EH. With generalized multifactor dimensionality reduction, a potential gene‑gene interaction between CpG6 and CpG8 (P=0.001), and gene‑environment interactions between smoking, alcohol consumption, CpG6, CpG7 and CpG8 (P=0.011), were observed. In conclusion, the results of the present study demonstrated that hypomethylation of the TLR2 promoter, particularly CpG6, was associated with the risk of EH in this population. Additionally, a gene‑gene interaction between CpG6 and CpG8, and interactions between environmental factors, including smoking and alcohol consumption, and CpG6, CpG7 and CpG8, may be associated with the risk of EH.

[1]  X. Niu,et al.  TLR2-ICAM1-Gadd45α Axis Mediates the Epigenetic Effect of Selenium on DNA Methylation and Gene Expression in Keshan Disease , 2014, Biological Trace Element Research.

[2]  P. Vokonas,et al.  Association between blood pressure and DNA methylation of retrotransposons and pro-inflammatory genes. , 2013, International journal of epidemiology.

[3]  Lina Zhang,et al.  Association of AGTR1 Promoter Methylation Levels with Essential Hypertension Risk: A Matched Case-Control Study , 2015, Cytogenetic and Genome Research.

[4]  Peng-Yuan Liu,et al.  Base-Resolution Maps of 5-Methylcytosine and 5-Hydroxymethylcytosine in Dahl S Rats: Effect of Salt and Genomic Sequence , 2014, Hypertension.

[5]  J. Freedman,et al.  Regulatory effects of TLR2 on megakaryocytic cell function. , 2011, Blood.

[6]  E. Podrez,et al.  Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands , 2010, Nature.

[7]  W. Kiosses,et al.  Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events , 2008, The Journal of experimental medicine.

[8]  Xueli Yang,et al.  Hypertension burden and control in mainland China: Analysis of nationwide data 2003-2012. , 2015, International journal of cardiology.

[9]  Yu-Chen Fan,et al.  Sera DNA Methylation of CDH1, DNMT3b and ESR1 Promoters as Biomarker for the Early Diagnosis of Hepatitis B Virus-Related Hepatocellular Carcinoma , 2016, Digestive Diseases and Sciences.

[10]  S. Murphy,et al.  Bisulfite pyrosequencing. , 2013, Methods in molecular biology.

[11]  Jun Zhu,et al.  A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. , 2007, American journal of human genetics.

[12]  2003 European Society of Hypertension-European Society of Cardiology Guidelines for the Management of Arterial Hypertension , 2004, Heart Drug.

[13]  L. Bautista,et al.  Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension , 2005, Journal of Human Hypertension.

[14]  K. Sung,et al.  High sensitivity C-reactive protein as an independent risk factor for essential hypertension. , 2003, American journal of hypertension.

[15]  C. Janeway,et al.  MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. , 1998, Molecular cell.

[16]  A. Bird,et al.  CpG islands and the regulation of transcription. , 2011, Genes & development.

[17]  K. Nakai,et al.  Genome-Wide Analysis of DNA Methylation and Expression of MicroRNAs in Breast Cancer Cells , 2012, International journal of molecular sciences.

[18]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[19]  G. Hansson,et al.  Expression of Toll-Like Receptors in Human Atherosclerotic Lesions: A Possible Pathway for Plaque Activation , 2002, Circulation.

[20]  S. Duan,et al.  Lower ADD1 Gene Promoter DNA Methylation Increases the Risk of Essential Hypertension , 2013, PloS one.

[21]  M. Yanagawa,et al.  Association Of Serum Tumour Necrosis Factor‐α With Serum Low‐Density Lipoprotein–Cholesterol And Blood Pressure In Apparently Healthy Japanese Women , 2001, Clinical and experimental pharmacology & physiology.

[22]  S. Taddei,et al.  Impact of inflammation on vascular disease in hypertension. , 2014, Maturitas.

[23]  A. Oliveras,et al.  Resistant hypertension: patient characteristics, risk factors, co-morbidities and outcomes , 2014, Journal of Human Hypertension.

[24]  L. O’Neill,et al.  Signal transduction pathways activated by the IL‐1 receptor family: ancient signaling machinery in mammals, insects, and plants , 1998, Journal of leukocyte biology.

[25]  Is C-reactive protein an independent risk factor for essential hypertension? , 2001, Journal of hypertension.

[26]  P. Vardas,et al.  TLR2 and TLR4 Gene Expression in Peripheral Monocytes in Nondiabetic Hypertensive Patients: The Effect of Intensive Blood Pressure–Lowering , 2012, Journal of clinical hypertension.

[27]  V. Richard,et al.  Toll-Like Receptors 2-Deficient Mice Are Protected Against Postischemic Coronary Endothelial Dysfunction , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[28]  J. Francis,et al.  Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension , 2015, Journal of Neuroinflammation.

[29]  P. Godowski,et al.  The apoptotic signaling pathway activated by Toll‐like receptor‐2 , 2000, The EMBO journal.

[30]  M. Abdolhosseini,et al.  TLR2 Promoter Hypermethylation Creates Innate Immune Dysbiosis , 2015, Journal of dental research.

[31]  H. Erdjument-Bromage,et al.  TLR signaling augments macrophage bactericidal activity through mitochondrial ROS , 2011, Nature.

[32]  M. Suico,et al.  Promoter hypomethylation of Toll‐like receptor‐2 gene is associated with increased proinflammatory response towardbacterial peptidoglycan in cystic fibrosis bronchial epithelial cells , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[34]  A. Rosenthal,et al.  Variations in DNA methylation during mouse cell differentiation in vivo and in vitro. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[35]  A. Akhmedov,et al.  Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. , 2013, Immunity.

[36]  Peter A. Jones,et al.  The Role of DNA Methylation in Mammalian Epigenetics , 2001, Science.

[37]  B. Morgenstern,et al.  Human blood pressure determination by sphygmomanometry. , 1993, Circulation.

[38]  Lina Zhang,et al.  Aberrant methylation of the GCK gene body is associated with the risk of essential hypertension. , 2015, Molecular medicine reports.

[39]  C. Sobey,et al.  Roles of Inflammation, Oxidative Stress, and Vascular Dysfunction in Hypertension , 2014, BioMed research international.

[40]  P. Ridker,et al.  Blood Pressure and Inflammation in Apparently Healthy Men , 2001, Hypertension.

[41]  I. Waczulíková,et al.  The value of SHOX2 methylation test in peripheral blood samples used for the differential diagnosis of lung cancer and other lung disorders. , 2016, Neoplasma.

[42]  A. Dobrovic,et al.  Analysing DNA methylation using bisulphite pyrosequencing. , 2011, Methods in molecular biology.