Hypomethylation of interleukin-6 (IL-6) gene increases the risk of essential hypertension: a matched case–control study

Article metrics

Subjects

Abstract

Essential hypertension (EH) is a chronic disease with clear epigenetic component. Inflammation and endothelial dysfunction have a great role in the development of persistent blood pressure elevation. The aim of this study was to explore an association between EH and DNA methylation in pro-inflammation cytokine gene interleukin-6 (IL-6) during the inflammatory process. We performed methylation analysis of peripheral blood DNA using bisulphite pyrosequencing technology between 96 EH patients and 96 age- and gender-matched healthy controls. The present results showed that three cytosine–phosphate–guanine (CpG) sites of IL-6 promoter CpG island had different lower methylation in EH group compared with controls, but only CpG2 (58.43±7.53 versus 62.34±9.65, P=0.004) and CpG3 (51.52±6.18 versus 57.45±8.29, P<0.001) had statistical difference. Logistic regression analysis found CpG3 hypomethylation was a risk factor of EH (odds ratio=1.111, adjusted P=0.004). In addition, we found hypermethylation of CpG1 (64.84±7.06 versus 61.84±8.61) and CpG2 (62.04±7.40 versus 59.30±9.57) in male compared with female. In male, we found hypomethylation of CpG2 (60.41±7.74 versus 64.28±6.36) and CpG3 (53.70±8.62 versus 57.78±7.87) of smoker versus non-smoker and hypomethylation of CpG2 (60.89±7.32 versus 64.70±7.03) and CpG3 (53.23±7.99 versus 60.48±7.58) of drinker versus non-drinker. Furthermore, the CpG2 and CpG3 had a negative correlation with systolic blood pressure and diastolic blood pressure (P<0.05). Receiver operating characteristic curve analysis showed that CpG2 (area under curve: 0.638, P=0.001) and CpG3 (area under curve: 0.704, P<0.001) had a diagnostic value to predict the risk of EH. In summary, our study revealed hypomethylation of IL-6 was correlated with the risk of EH in the population assessed and we found the differences of IL-6 promoter methylation in gender, smoking and drinking.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. 1

    Wang Y, Nie X, Chen L, Weldon R, Zhang W, Xiao D et al. Burden of hypertension in China over the past decades: systematic analysis of prevalence, treatment and control of hypertension. Eur J Prev Cardiol 2015; 23: 792–800.

  2. 2

    Bautista L, Vera L, Arenas I, Gamarra G . Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension. J Hum Hypertens 2005; 19: 149–154.

  3. 3

    Chae CU, Lee RT, Rifai N, Ridker PM . Blood pressure and inflammation in apparently healthy men. Hypertension 2001; 38: 399–403.

  4. 4

    Dinh QN, Drummond GR, Sobey CG, Chrissobolis S . Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. BioMed Res Int 2014; 2014: 406960.

  5. 5

    Ridker PM, Buring JE, Cook NR, Rifai N . C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003; 107: 391–397.

  6. 6

    Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000; 321: 199–204.

  7. 7

    Ikeda U, Ikeda M, Oohara T, Oguchi A, Kamitani T, Tsuruya Y et al. Interleukin 6 stimulates growth of vascular smooth muscle cells in a PDGF-dependent manner. Am J Physiol 1991; 260: H1713–H1717.

  8. 8

    Fernandez-Real J-M, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J et al. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 2001; 86: 1154–1159.

  9. 9

    Kranzhöfer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kübler W . Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999; 19: 1623–1629.

  10. 10

    Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M et al. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques potential implications for inflammation and plaque instability. Circulation 2000; 101: 1372–1378.

  11. 11

    Bennermo M, Nordin M, Lundman P, Boqvist S, Held C, Samnegård A et al. Genetic and environmental influences on the plasma interleukin-6 concentration in patients with a recent myocardial infarction: a case-control study. J Interferon Cytokine Res 2011; 31: 259–264.

  12. 12

    Brull D, Lesson C, Montgomery H, Mullen M, DeDivitiis M, Humphries S et al. The effect of the Interleukin-6–174G&gt; C promoter gene polymorphism on endothelial function in healthy volunteers. Eur J Clin Invest 2002; 32: 153–157.

  13. 13

    Razin A, Webb C, Szyf M, Yisraeli J, Rosenthal A, Naveh-Many T et al. Variations in DNA methylation during mouse cell differentiation in vivo and in vitro. Proc Natl Acad Sci 1984; 81: 2275–2279.

  14. 14

    Deaton AM, Bird A . CpG islands and the regulation of transcription. Genes Dev 2011; 25: 1010–1022.

  15. 15

    Shen H, Laird PW . Interplay between the cancer genome and epigenome. Cell 2013; 153: 38–55.

  16. 16

    Hinoue T, Weisenberger DJ, Lange CP, Shen H, Byun HM, Van Den Berg D et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 2012; 22: 271–282.

  17. 17

    Movassagh M, Choy MK, Knowles DA, Cordeddu L, Haider S, Down T et al. Distinct epigenomic features in end-stage failing human hearts. Circulation 2011; 124: 2411–2422.

  18. 18

    Talens RP, Jukema JW, Trompet S, Kremer D, Westendorp RG, Lumey LH et al. Hypermethylation at loci sensitive to the prenatal environment is associated with increased incidence of myocardial infarction. Int J Epidemiol 2012; 41: 106–115.

  19. 19

    Volkmar M, Dedeurwaerder S, Cunha DA, Ndlovu MN, Defrance M, Deplus R et al. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 2012; 31: 1405–1426.

  20. 20

    Nile CJ, Read RC, Akil M, Duff GW, Wilson AG . Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 2008; 58: 2686–2693.

  21. 21

    de Andrés MC, Imagawa K, Hashimoto K, Gonzalez A, Roach HI, Goldring MB et al. Loss of methylation in CpG sites in the NF-κB enhancer elements of inducible nitric oxide synthase is responsible for gene induction in human articular chondrocytes. Arthritis Rheum 2013; 65: 732–742.

  22. 22

    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 2003; 21: 1011–1053.

  23. 23

    Perloff D, Grim C, Flack J, Frohlich ED, Hill M, McDonald M et al. Human blood pressure determination by sphygmomanometry. Circulation 1993; 88: 2460–2470.

  24. 24

    Bassil CF, Huang Z, Murphy SK . Bisulfite pyrosequencing. Methods Mol Biol 2013; 1049: 95–107.

  25. 25

    Mikeska T, Felsberg J, Hewitt CA, Dobrovic A . Analysing DNA methylation using bisulphite pyrosequencing. Methods Mol Biol 2011; 791: 33–53.

  26. 26

    Mahmud A, Feely J . Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension 2005; 46: 1118–1122.

  27. 27

    Bautista LE, Vera LM, Arenas IA, Gamarra G . Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. J Hum Hypertens 2005; 19: 149–154.

  28. 28

    Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1998; 19: 187–191.

  29. 29

    Morita S, Takahashi RU, Yamashita R, Toyoda A, Horii T, Kimura M et al. Genome-wide analysis of DNA methylation and expression of microRNAs in breast cancer cells. Int J Mol Sci 2012; 13: 8259–8272.

  30. 30

    Nile CJ, Read RC, Akil M, Duff GW, Wilson AG . Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 2008; 58: 2686–2693.

  31. 31

    Tekpli X, Landvik NE, Anmarkud KH, Skaug V, Haugen A, Zienolddiny S . DNA methylation at promoter regions of interleukin 1B, interleukin 6, and interleukin 8 in non-small cell lung cancer. Cancer Immunol Immunother 2013; 62: 337–345.

  32. 32

    Armenante F, Merola M, Furia A, Palmieri M . Repression of the IL-6 gene is associated with hypermethylation. Biochem Biophys Res Commun 1999; 258: 644–647.

  33. 33

    Zhang FF, Cardarelli R, Carroll J, Fulda KG, Kaur M, Gonzalez K et al. Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics 2011; 6: 623–629.

  34. 34

    Hsiung DT, Marsit CJ, Houseman EA, Eddy K, Furniss CS, McClean MD et al. Global DNA methylation level in whole blood as a biomarker in head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 2007; 16: 108–114.

  35. 35

    El-Maarri O, Becker T, Junen J, Manzoor SS, Diaz-Lacava A, Schwaab R et al. Gender specific differences in levels of DNA methylation at selected loci from human total blood: a tendency toward higher methylation levels in males. Hum Genet 2007; 122: 505–514.

  36. 36

    Cotton AM, Lam L, Affleck JG, Wilson IM, Penaherrera MS, McFadden DE et al. Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation. Hum Genet 2011; 130: 187–201.

  37. 37

    Zhang LN, Liu PP, Wang L, Yuan F, Xu L, Xin Y et al. Lower ADD1 gene promoter DNA methylation increases the risk of essential hypertension. PLoS ONE 2013; 8: e63455.

  38. 38

    Woodson K, Mason J, Choi SW, Hartman T, Tangrea J, Virtamo J et al. Hypomethylation of p53 in peripheral blood DNA is associated with the development of lung cancer. Cancer Epidemiol Biomarkers Prev 2001; 10: 69–74.

  39. 39

    Marsit CJ, McClean MD, Furniss CS, Kelsey KT . Epigenetic inactivation of the SFRP genes is associated with drinking, smoking and HPV in head and neck squamous cell carcinoma. Int J Cancer 2006; 119: 1761–1766.

  40. 40

    Marutha Ravindran CR, Ticku MK . Role of CpG islands in the up-regulation of NMDA receptor NR2B gene expression following chronic ethanol treatment of cultured cortical neurons of mice. Neurochem Int 2005; 46: 313–327.

  41. 41

    Nishihara R, Wang M, Qian ZR, Baba Y, Yamauchi M, Mima K et al. Alcohol, one-carbon nutrient intake, and risk of colorectal cancer according to tumor methylation level of IGF2 differentially methylated region. Am J Clin Nutr 2014; 100: 1479–1488.

  42. 42

    Alexeeff SE, Baccarelli AA, Halonen J, Coull BA, Wright RO, Tarantini L et al. Association between blood pressure and DNA methylation of retrotransposons and pro-inflammatory genes. Int J Epidemiol 2013; 42: 270–280.

Download references

Acknowledgements

This research was supported by Zhejiang Province Social development Research Project (2016C33178), K.C. Wong Magna Fund in Ningbo University, Ningbo Social Development Research Project (2014C50051), Ningbo Scientific Innovation Team for Environment Hazardous Factor Control and Prevention (2016C51001). Ningbo Medical Science and Technology Plan Project (2013A39), the Scientific Research Innovation Foundation of Ningbo University (G16097) and the Scientific Research Innovation Foundation of Ningbo University (G15070).

Author information

Correspondence to F-y Yin or L-n Zhang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading