Aberrant methylation of the GCK gene body is associated with the risk of essential hypertension

Fan,Rui; Wang,Wei‑Jie; Zhong,Qi-Long; Duan,Shi-Wei; Xu,Xu‑Ting; Hao,Ling‑Mei; Zhao,Jing; Zhang,Li-Na

doi:10.3892/mmr.2015.3631

Aberrant methylation of the GCK gene body is associated with the risk of essential hypertension

Authors:
- Rui Fan
- Wei‑Jie Wang
- Qi-Long Zhong
- Shi-Wei Duan
- Xu‑Ting Xu
- Ling‑Mei Hao
- Jing Zhao
- Li-Na Zhang
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Affiliations: Department of Preventive Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China, Department of General Medicine, Ningbo Baizhang Street Community Health Service Center, Ningbo, Zhejiang 315211, P.R. China , Clinical Laboratory, The Seventh Hospital of Ningbo, Ningbo, Zhejiang 315211, P.R. China
Published online on: April 16, 2015 https://doi.org/10.3892/mmr.2015.3631
Pages: 2390-2394

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Abstract

Essential hypertension (EH) is commonly accompanied by a dysfunction of glucose metabolism. Glucokinase (GCK) is a key enzyme involved in glucose metabolism. The aim of the present study was to investigate whether GCK gene‑body methylation contributed to the risk of EH. A total of 47 patients with EH and 47 age‑matched controls were recruited for methylation research in the current study. GCK gene‑body methylation was measured using bisulphite pyrosequencing technology. DNA methylation levels were closely correlated among CpG1, CpG2 and CpG3 (r>0.70; P<0.001), in contrast with a weaker correlation between CpG4 and the preceding three CpGs (r<0.3 or r=1; P>0.05). Significantly lower CpG1‑3 methylation (cases vs. controls, 49.13±5.72 vs. 53.49±7.53%; adjusted P=0.006) and significantly higher CpG4 methylation (cases vs. controls, 46.34±6.48 vs. 34.74±12.73%; adjusted P=0.002) were observed in patients with EH. The present study indicated that aberrant methylation of the GCK gene body was significantly associated with the risk of EH in the population assessed. The discrepancies between CpG1‑3 and CpG4 methylation may suggest distinct roles for each of them in the determination of the risk of EH.

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1	Lawes CM, Vander Hoorn S and Rodgers A; International Society of Hypertension: Global burden of blood-pressure-related disease, 2001. Lancet. 371:1513–1518. 2008. View Article : Google Scholar : PubMed/NCBI
2	Xi B, Cheng H, Shen Y, et al: Physical activity modifies the associations between genetic variants and hypertension in the Chinese children. Atherosclerosis. 225:376–380. 2012. View Article : Google Scholar : PubMed/NCBI
3	Tanira MO and Al Balushi KA: Genetic variations related to hypertension: A review. J Hum Hypertens. 19:7–19. 2005. View Article : Google Scholar
4	Xi B, Shen Y, Reilly KH, Wang X and Mi J: Recapitulation of four hypertension susceptibility genes (CSK, CYP17A1, MTHFR and FGF5) in East Asians. Metabolism. 62:196–203. 2013. View Article : Google Scholar
5	Xi B, Tang W and Wang Q: Polymorphism near the ATP2B1 gene is associated with hypertension risk in East Asians: A meta-analysis involving 15909 cases and 18529 controls. Blood Press. 21:134–138. 2012. View Article : Google Scholar : PubMed/NCBI
6	Binder A: A review of the genetics of essential hypertension. Curr Opin Cardiol. 22:176–184. 2007. View Article : Google Scholar : PubMed/NCBI
7	Whelton PK, He J, Appel LJ, et al: Primary prevention of hypertension: Clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. 288:1882–1888. 2002. View Article : Google Scholar : PubMed/NCBI
8	Jjingo D, Conley AB, Yi SV, Lunyak VV and Jordan IK: On the presence and role of human gene-body DNA methylation. Oncotarget. 3:462–474. 2012.PubMed/NCBI
9	Zemach A, McDaniel IE, Silva P and Zilberman D: Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science. 328:916–919. 2010. View Article : Google Scholar : PubMed/NCBI
10	Kim MS, Lee J and Sidransky D: DNA methylation markers in colorectal cancer. Cancer Metastasis Rev. 29:181–206. 2010. View Article : Google Scholar : PubMed/NCBI
11	Kerr KM, Galler JS, Hagen JA, Laird PW and Laird-Offringa IA: The role of DNA methylation in the development and progression of lung adenocarcinoma. Dis Markers. 23:5–30. 2007. View Article : Google Scholar : PubMed/NCBI
12	Akalin A, Garrett-Bakelman FE, Kormaksson M, et al: Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. PLoS Genet. 8:e10027812012. View Article : Google Scholar : PubMed/NCBI
13	Smolarek I, Wyszko E, Barciszewska AM, et al: Global DNA methylation changes in blood of patients with essential hypertension. Med Sci Monit. 16:CR149–CR155. 2010.PubMed/NCBI
14	Kulkarni A, Chavan-Gautam P, Mehendale S, Yadav H and Joshi S: Global DNA methylation patterns in placenta and its association with maternal hypertension in pre-eclampsia. DNA Cell Biol. 30:79–84. 2011. View Article : Google Scholar
15	Friso S, Pizzolo F, Choi SW, et al: Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension. Atherosclerosis. 199:323–327. 2008. View Article : Google Scholar : PubMed/NCBI
16	Zhang LN, Liu PP, Wang L, et al: Lower ADD1 gene promoter DNA methylation increases the risk of essential hypertension. PLoS One. 8:e634552013. View Article : Google Scholar : PubMed/NCBI
17	Liu J, Zhao D, Liu J, Qi Y, Sun J and Wang W: Prevalence of diabetes mellitus in outpatients with essential hypertension in China: A cross-sectional study. BMJ Open. 3:e0037982013. View Article : Google Scholar : PubMed/NCBI
18	Iynedjian PB: Molecular physiology of mammalian glucokinase. Cell Mol Life Sci. 66:27–42. 2009. View Article : Google Scholar :
19	Heredia VV, Thomson J, Nettleton D and Sun S: Glucose-induced conformational changes in glucokinase mediate allosteric regulation: Transient kinetic analysis. Biochemistry. 45:7553–7562. 2006. View Article : Google Scholar : PubMed/NCBI
20	Kamata K, Mitsuya M, Nishimura T, Eiki Ji and Nagata Y: Structural basis for allosteric regulation of the monomeric allo-steric enzyme human glucokinase. Structure. 12:429–438. 2004. View Article : Google Scholar : PubMed/NCBI
21	Chiang FT, Chiu KC, Tseng YZ, Lee KC and Chuang LM: Nucleotide(-258) G-to-A transition variant of the liver glucokinase gene is associated with essential hypertension. Am J Hypertens. 10:1049–1052. 1997. View Article : Google Scholar : PubMed/NCBI
22	Yamada Y, Ando F and Shimokata H: Association of polymorphisms of SORBS1, GCK and WISP1 with hypertension in community-dwelling Japanese individuals. Hypertens Res. 32:325–331. 2009. View Article : Google Scholar : PubMed/NCBI
23	Xu L, Zheng D, Wang L, et al: GCK gene-body hypomethylation is associated with the risk of coronary heart disease. Biomed Res Int. 2014:72014. View Article : Google Scholar
24	MacMahon S, Peto R, Collins R, et al: Blood pressure, stroke and coronary heart disease: Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 335:765–774. 1990. View Article : Google Scholar : PubMed/NCBI
25	Nadeem M, Ahmed SS, Mansoor S and Farooq S: Risk factors for coronary heart disease in patients below 45 years of age. Pak J Med Sci. 29:91–96. 2013.PubMed/NCBI
26	European Society of Hypertension-European Society of Cardiology Guidelines Committee: 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 21:1011–1053. 2003. View Article : Google Scholar : PubMed/NCBI
27	Perloff D, Grim C, Flack J, et al: Human blood pressure determination by sphygmomanometry. Circulation. 88:2460–2470. 1993. View Article : Google Scholar : PubMed/NCBI
28	Jiang D, Zheng D, Wang L, et al: Elevated PLA2G7 gene promoter methylation as a gender-specific marker of aging increases the risk of coronary heart disease in females. PLoS One. 8:e597522013. View Article : Google Scholar : PubMed/NCBI
29	Bassil CF, Huang Z and Murphy SK: Bisulfite pyrosequencing. Methods Mol Biol. 1049:95–107. 2013.PubMed/NCBI
30	Illingworth RS, Gruenewald-Schneider U, Webb S, et al: Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genet. 6:e10011342010. View Article : Google Scholar : PubMed/NCBI
31	Maunakea AK, Nagarajan RP, Bilenky M, et al: Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 466:253–257. 2010. View Article : Google Scholar : PubMed/NCBI
32	Movassagh M, Choy MK, Knowles DA, et al: Distinct epigenomic features in end-stage failing human hearts. Circulation. 124:2411–2422. 2011. View Article : Google Scholar : PubMed/NCBI
33	Jones PA: Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat Rev Genet. 13:484–492. 2012. View Article : Google Scholar : PubMed/NCBI
34	Aran D, Toperoff G, Rosenberg M and Hellman A: Replication timing-related and gene body-specific methylation of active human genes. Hum Mol Genet. 20:670–680. 2011. View Article : Google Scholar
35	Ball MP, Li JB, Gao Y, et al: Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 27:361–368. 2009. View Article : Google Scholar : PubMed/NCBI
36	Cambien F, Warnet JM, Eschwege E, Jacqueson A, Richard JL and Rosselin G: Body mass, blood pressure, glucose, and lipids. Does plasma insulin explain their relationships? Arteriosclerosis. 7:197–202. 1987. View Article : Google Scholar : PubMed/NCBI
37	Cheung BM, Ong KL, Tso AW, et al: Gamma-glutamyl trans-ferase level predicts the development of hypertension in Hong Kong Chinese. Clin Chim Acta. 412:1326–1331. 2011. View Article : Google Scholar : PubMed/NCBI
38	Chen DL, Zhang CJ, Fu YH, Mo YJ and Chen FR: Correlation of angiotensin-converting enzyme 2 gene polymorphisms to essential hypertension and ischemic stroke. Nan Fang Yi Ke Da Xue Xue Bao. 30:1890–1892. 2010.In Chinese.