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Association of gene polymorphisms in RANKL/RANK/OPG system with hypertension and blood pressure in Chinese women

Journal of Human Hypertension volume 29, pages 749–753 (2015)Cite this article

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Abstract

Recent studies have revealed that the receptor activator of nuclear factor-kappa B ligand/RANK/osteoprotegerin (RANKL/RANK/OPG) system has an important role in vascular calcification, which is contributory to various cardiovascular diseases and intimately linked to the regulation of blood pressure. Therefore, we performed a case–control study to investigate the associations of 21 single-nucleotide polymorphisms (SNPs) in the TNFSF11, TNFRSF11A and TNFRSF11B genes in the RANKL/RANK/OPG system with hypertension and blood pressure in post-menopausal Chinese women. In this study, 503 hypertensive patients and 509 normal controls were recruited. Genotyping was performed using the high-throughput Sequenom genotyping platform. The results showed that two SNPs (rs6567270 and rs4603673) in the TNFRSF11A were associated with hypertension (P=0.010 and P=0.013, respectively) and systolic blood pressure (P=0.024 and P=0.023, respectively). One SNP (rs9646629) in the TNFRSF11A showed significant association with diastolic blood pressure (P=0.031). The results of this study suggest that TNFRSF11A but not TNFSF11 and TNFRSF11B genetic variation is associated with hypertension and blood pressure in Chinese women. The findings provide additional support for the genetic role of RANKL/RANK/OPG system in hypertension and blood pressure regulation.

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References

  1. Sliwa K, Stewart S, Gersh BJ . Hypertension: a global perspective. Circulation 2011; 123: 2892–2896.

    Article  Google Scholar 

  2. Wu Y, Huxley R, Li L, Anna V, Xie G, Yao C et al. Prevalence, awareness, treatment, and control of hypertension in China: data from the China National Nutrition and Health Survey 2002. Circulation 2008; 118: 2679–2686.

    Article  Google Scholar 

  3. Wang J, Zhang L, Wang F, Liu L, Wang H and China National Survey of Chronic Kidney Disease Working Group. Prevalence, Awareness, Treatment, and Control of Hypertension in China: Results From a National Survey. Am J Hypertens 2014; 27: 1355–1361.

    Article  CAS  Google Scholar 

  4. Hottenga JJ, Boomsma DI, Kupper N, Posthuma D, Snieder H, Willemsen G et al. Heritability and stability of resting blood pressure. Twin Res Hum Genet 2005; 8: 499–508.

    Article  Google Scholar 

  5. Wu T, Snieder H, Li L, Cao W, Zhan S, Lv J et al. Genetic and environmental influences on blood pressure and body mass index in Han Chinese: a twin study. Hypertens Res 2011; 34: 173–179.

    Article  Google Scholar 

  6. Liu Y, Lou YQ, Liu K, Liu JL, Wang ZG, Wen J et al. Role of leptin receptor gene polymorphisms in susceptibility to the development of essential hypertension: a case-control association study in a Northern Han Chinese population. J Hum Hypertens 2014; 28: 551–556.

    Article  CAS  Google Scholar 

  7. Chiang KM, Yang HC, Liang YJ, Chen JW, Hwang SM, Ho HY et al. A three-stage genome-wide association study combining multilocus test and gene expression analysis for young-onset hypertension in taiwan han chinese. Am J Hypertens 2014; 27: 819–827.

    Article  CAS  Google Scholar 

  8. Rao AD, Sun B, Saxena A, Hopkins PN, Jeunemaitre X, Brown NJ et al. Polymorphisms in the serum- and glucocorticoid-inducible kinase 1 gene are associated with blood pressure and renin response to dietary salt intake. J Hum Hypertens 2013; 27: 176–180.

    Article  CAS  Google Scholar 

  9. Xiong J, O'Brien CA . Osteocyte RANKL: new insights into the control of bone remodeling. J Bone Miner Res 2012; 27: 499–505.

    Article  CAS  Google Scholar 

  10. Papadopouli AE, Klonaris CN, Theocharis SE . Role of OPG/RANKL/RANK axis on the vasculature. Histol Histopathol 2008; 23: 497–506.

    CAS  PubMed  Google Scholar 

  11. Hofbauer LC, Schoppet M . Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490–495.

    Article  CAS  Google Scholar 

  12. Montagnana M, Lippi G, Danese E, Guidi GC . The role of osteoprotegerin in cardiovascular disease. Ann Med 2013; 45: 254–264.

    Article  CAS  Google Scholar 

  13. Rasmussen LM, Tarnow L, Hansen TK, Parving HH, Flyvbjerg A . Plasma osteoprotegerin levels are associated with glycaemic status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1 diabetic patients. Eur J Endocrinol 2006; 154: 75–81.

    Article  CAS  Google Scholar 

  14. Zagura M, Serg M, Kampus P, Zilmer M, Zilmer K, Eha J et al. Association of osteoprotegerin with aortic stiffness in patients with symptomatic peripheral artery disease and in healthy subjects. Am J Hypertens 2010; 23: 586–591.

    Article  CAS  Google Scholar 

  15. Røysland R, Bonaca MP, Omland T, Sabatine M, Murphy SA, Scirica BM et al. Osteoprotegerin and cardiovascular mortality in patients with non-ST elevation acute coronary syndromes. Heart 2012; 98: 786–791.

    Article  Google Scholar 

  16. Van Campenhout A, Golledge J . Osteoprotegerin, vascular calcification and atherosclerosis. Atherosclerosis 2009; 204: 321–329.

    Article  CAS  Google Scholar 

  17. Rattazzi M, Bertacco E, Puato M, Faggin E, Pauletto P . Hypertension and vascular calcification: a vicious cycle? J Hypertens 2012; 30: 1885–1893.

    Article  CAS  Google Scholar 

  18. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  19. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  Google Scholar 

  20. Golledge J, Biros E, Clancy P, Cooper M, Palmer LJ, Norman PE . A single-nucleotide polymorphism in the gene encoding osteoprotegerin is associated with diastolic blood pressure in older men. Am J Hypertens 2009; 22: 1167–1170.

    Article  CAS  Google Scholar 

  21. Choe WS, Kim HL, Han JK, Choi YE, Seo B, Cho HJ et al. Association between OPG, RANK and RANKL gene polymorphisms and susceptibility to acute coronary syndrome in Korean population. J Genet 2012; 91: 87–89.

    Article  Google Scholar 

  22. Rhee EJ, Yun EJ, Oh KW, Park SE, Park CY, Lee WY et al. The relationship between Receptor Activator of Nuclear Factor-kappaB Ligand (RANKL) gene polymorphism and aortic calcification in Korean women. Endocr J 2010; 57: 541–549.

    Article  CAS  Google Scholar 

  23. Brändström H, Stiger F, Lind L, Kahan T, Melhus H, Kindmark A . A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function. Biochem Biophys Res Commun 2002; 293: 13–17.

    Article  Google Scholar 

  24. Brändström H, Stiger F, Kahan T, Melhus H, Nyström F, öHman KP et al. A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients. The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA). Blood Press 2004; 13: 152–157.

    Article  Google Scholar 

  25. Kawai T, Ohishi M, Ito N, Onishi M, Takeya Y, Yamamoto K et al. Alteration of vascular function is an important factor in the correlation between visit-to-visit blood pressure variability and cardiovascular disease. J Hypertens 2013; 31: 1387–1395.

    Article  CAS  Google Scholar 

  26. Thanassoulis G, Lyass A, Benjamin EJ, Larson MG, Vita JA, Levy D et al. Relations of exercise blood pressure response to cardiovascular risk factors and vascular function in the Framingham Heart Study. Circulation 2012; 125: 2836–2843.

    Article  Google Scholar 

  27. Collin-Osdoby P . Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004; 95: 1046–1057.

    Article  CAS  Google Scholar 

  28. Kalra SS, Shanahan CM . Vascular calcification and hypertension: cause and effect. Ann Med 2012; 44: S85–S92.

    Article  CAS  Google Scholar 

  29. Tousoulis D, Siasos G, Maniatis K, Oikonomou E, Kioufis S, Zaromitidou M et al. Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease. Int J Cardiol 2013; 167: 1924–1928.

    Article  Google Scholar 

  30. Huang JW, Lien YC, Yang CY, Liu KL, Wu CF, Yen CJ et al. Osteoprotegerin, inflammation and dyslipidemia are associated with abdominal aortic calcification in non-diabetic patients on peritoneal dialysis. Nutr Metab Cardiovasc Dis 2014; 24: 236–242.

    Article  CAS  Google Scholar 

  31. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260–1268.

    Article  CAS  Google Scholar 

  32. Panizo S, Cardus A, Encinas M, Parisi E, Valcheva P, López-Ongil S et al. RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circ Res 2009; 104: 1041–1048.

    Article  CAS  Google Scholar 

  33. Shin JY, Shin YG, Chung CH . Elevated serum osteoprotegerin levels are associated with vascular endothelial dysfunction in type 2 diabetes. Diabetes Care 2006; 29: 1664–1666.

    Article  CAS  Google Scholar 

  34. Zhang W, Wang Q, Wu Y, Moriasi C, Liu Z, Dai X et al. Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo. Circulation 2014; 129: 1428–1439.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (no. 81260133) and the Key Projects of Health Department of Jiangxi province, China (no. 20114030).

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  1. Department of Endocrinology and Metabolism, Nanchang Key Laboratory of Diabetes, The Third Hospital of Nanchang, Nanchang city, People’s Republic of China

    P Duan, Z-M Wang, J Liu, L-N Wang, Z Yang & P Tu

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Correspondence to P Tu.

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Duan, P., Wang, ZM., Liu, J. et al. Association of gene polymorphisms in RANKL/RANK/OPG system with hypertension and blood pressure in Chinese women. J Hum Hypertens 29, 749–753 (2015). https://doi.org/10.1038/jhh.2015.13

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