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Association of common variants in/near six genes (ATP2B1, CSK, MTHFR, CYP17A1, STK39 and FGF5) with blood pressure/hypertension risk in Chinese children

Abstract

Recent genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) that are associated with blood pressure (BP)/hypertension. In this study, we aimed to examine the established associations amongst Chinese children. We genotyped six SNPs (ATP2B1 rs17249754, CSK rs1378942, MTHFR rs1801133, CYP17A1 rs1004467, STK39 rs3754777 and FGF5 rs16998073) in Chinese children (N=3077, age range, 6–18 years). Based on the Chinese age- and sex-specific BP standards, 619 hypertensive cases and 2458 controls with normal BP were identified. Of the six SNPs, only ATP2B1 rs17249754 SNP was significantly associated with the risk of hypertension (allelic odds ratio (OR)=1.25, 95% confidence interval (CI): 1.08–1.44, P=0.003). Although all other SNPs showed a trend towards increasing the BP values and risk of hypertension, there was no statistically significant association after false discovery rate analysis. We calculated the weighted risk score using six SNPs, for systolic BP (SBP), diastolic BP (DBP) and hypertension. Each additional weighted risk score was associated with SBP by 1.18 mm Hg (95% CI=0.62–1.73, P<0.001), but not with the DBP (β=0.28, 95% CI=(-0.15)-0.74), and overall increased the risk of hypertension by 1.19-fold (95% CI=1.04–1.35, P=0.01). The present study confirmed the significant association of ATP2B1 rs17249754 with risk of hypertension among Chinese children, but failed to replicate the association of CSK rs1378942, MTHFR rs1801133, CYP17A1 rs1004467, STK39 rs3754777 and FGF5 rs16998073 with BP/risk of hypertension.

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References

  1. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R and Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–1913.

    Article  Google Scholar 

  2. Chen X, Wang Y . Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation 2008; 117: 3171–3180.

    Article  Google Scholar 

  3. Xi B, Cheng H, Shen Y, Zhao X, Hou D, Wang X et al. Physical activity modifies the associations between genetic variants and hypertension in the Chinese children. Atherosclerosis 2012; 225: 376–380.

    Article  CAS  Google Scholar 

  4. Xi B, He D, Wang Q, Xue J, Liu M, Li J . Common polymorphisms (rs2241766 and rs1501299) in the ADIPOQ gene are not associated with hypertension susceptibility among the Chinese. Mol Biol Rep 2012; 39: 8771–8775.

    Article  CAS  Google Scholar 

  5. Xi B, Wang Q, Pan H . Transforming growth factor-β1 gene +869 T/C, but not +915 G/C polymorphism is associated with essential hypertension in a Chinese patient cohort. Mol Biol Rep 2012; 39: 6107–6112.

    Article  CAS  Google Scholar 

  6. Xi B, Shen Y, Yan Y, Mi J . Association of polymorphisms in the AGT gene with essential hypertension in the Chinese population. J Renin Angiotensin Aldosterone Syst 2012; 13: 282–288.

    Article  CAS  Google Scholar 

  7. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 2009; 41: 527–534.

    Article  CAS  Google Scholar 

  8. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 2009; 41: 666–676.

    Article  CAS  Google Scholar 

  9. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A et al. Genome-wide association study of blood pressure and hypertension. Nat Genet 2009; 41: 677–687.

    Article  CAS  Google Scholar 

  10. Wang Y, O'Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ et al. Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci USA 2009; 106: 226–231.

    Article  CAS  Google Scholar 

  11. Kato N, Takeuchi F, Tabara Y, Kelly TN, Go MJ, Sim X et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet 2011; 43: 531–538.

    Article  CAS  Google Scholar 

  12. International Consortium for Blood Pressure Genome-Wide Association Studies, Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011; 478: 103–109.

    Article  Google Scholar 

  13. Xi B, Tang W, Wang Q . Polymorphism near the ATP2B1 gene is associated with hypertension risk in East Asians: a meta-analysis involving 15 909 cases and 18 529 controls. Blood Press 2012; 21: 134–138.

    Article  CAS  Google Scholar 

  14. Xi B, Shen Y, Reilly KH, Wang X, Mi J . Recapitulation of four hypertension susceptibility genes (CSK, CYP17A1, MTHFR, and FGF5) in East Asians. Metabolism 2013; 62: 196–203.

    Article  CAS  Google Scholar 

  15. Shan XY, Xi B, Cheng H, Hou DQ, Wang Y, Mi J . Prevalence and behavioral risk factors of overweight and obesity among children aged 2–18 in Beijing, China. Int J Pediatr Obes 2010; 5: 383–389.

    Article  Google Scholar 

  16. Mi J, Wang TY, Meng LH, Zhu GJ, Han SM, Zhong Y et al. Development of blood pressure reference standards for Chinese children and adolescents. Chin J Evid Based Pediatr 2010; 5: 4–14.

    Google Scholar 

  17. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004; 114: 555–576.

    Article  Google Scholar 

  18. Qian X, Lu Z, Tan M, Liu H, Lu D . A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension. Eur J Hum Genet 2007; 15: 1239–1245.

    Article  CAS  Google Scholar 

  19. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc B 1995; 57: 289–300.

    Google Scholar 

  20. Hong KW, Go MJ, Jin HS, Lim JE, Lee JY, Han BG et al. Genetic variations in ATP2B1, CSK, ARSG and CSMD1 loci are related to blood pressure and/or hypertension in two Korean cohorts. J Hum Hypertens 2010; 24: 367–372.

    Article  CAS  Google Scholar 

  21. Liu C, Li H, Qi Q, Lu L, Gan W, Loos RJ et al. Common variants in or near FGF5, CYP17A1 and MTHFR genes are associated with blood pressure and hypertension in Chinese Hans. J Hypertens 2011; 29: 70–75.

    Article  Google Scholar 

  22. Tabara Y, Kohara K, Kita Y, Hirawa N, Katsuya T, Ohkubo T et al. Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project. Hypertension 2010; 56: 973–980.

    Article  CAS  Google Scholar 

  23. Takeuchi F, Isono M, Katsuya T, Yamamoto K, Yokota M, Sugiyama T et al. Blood pressure and hypertension are associated with 7 loci in the Japanese population. Circulation 2010; 121: 2302–2309.

    Article  Google Scholar 

  24. Miyaki K, Htun NC, Song Y, Ikeda S, Muramatsu M, Shimbo T . The combined impact of 12 common variants on hypertension in Japanese men, considering GWAS results. J Hum Hypertens 2012; 26: 430–436.

    Article  CAS  Google Scholar 

  25. Pande J, Mallhi KK, Sawh A, Szewczyk MM, Simpson F, Grover AK . Aortic smooth muscle and endothelial plasma membrane Ca2+ pump isoforms are inhibited differently by the extracellular inhibitor caloxin 1b1. Am J Physiol Cell Physiol 2006; 290: 1341–1349.

    Article  Google Scholar 

  26. Liu L, Ishida Y, Okunade G, Shull GE, Paul RJ . Role of plasma membrane Ca2-ATPase in contraction-relaxation processes of the bladder: evidence from PMCA gene-ablated mice. Am J Physiol Cell Physiol 2006; 290: 1239–1247.

    Article  Google Scholar 

  27. Monteith GR, Kable EP, Kuo TH, Roufogalis BD . Elevated plasma membrane and sarcoplasmic reticulum Ca2+ pump mRNA levels in cultured aortic smooth muscle cells from spontaneously hypertensive rats. Biochem Biophys Res Commun 1997; 230: 344–346.

    Article  CAS  Google Scholar 

  28. Rhee MY, Yang SJ, Oh SW, Park Y, Kim CI, Park HK et al. Novel genetic variations associated with salt sensitivity in the Korean population. Hypertens Res 2011; 34: 606–611.

    Article  CAS  Google Scholar 

  29. Niu W, Zhang Y, Ji K, Gu M, Gao P, Zhu D . Confirmation of top polymorphisms in hypertension genome wide association study among Han Chinese. Clin Chim Acta 2010; 411: 1491–1495.

    Article  CAS  Google Scholar 

  30. Wu L, Xi B, Zhang M, Shen Y, Zhao X, Wang T et al. A sex-specific effect of the CYP17A1 SNP rs11191548 on blood pressure in Chinese children. J Hum Hypertens 2012; 26: 731–736.

    Article  CAS  Google Scholar 

  31. Chen LY, Zhao WH, Tian W, Guo J, Jiang F, Jin LJ et al. STK39 is an independent risk factor for male hypertension in Han Chinese. Int J Cardiol 2012; 154: 122–127.

    Article  Google Scholar 

  32. Fava C, Danese E, Montagnana M, Sjögren M, Almgren P, Engström G et al. Serine/threonine kinase 39 is a candidate gene for primary hypertension especially in women: results from two cohort studies in Swedes. J Hypertens 2011; 29: 484–491.

    Article  CAS  Google Scholar 

  33. Cunnington MS, Kay C, Avery PJ, Mayosi BM, Koref MS, Keavney B . STK39 polymorphisms and blood pressure: an association study in British Caucasians and assessment of cis-acting influences on gene expression. BMC Med Genet 2009; 10: 135.

    Article  Google Scholar 

  34. Niu WQ, Zhang Y, Ji KD, Gao PJ, Zhu DL . Contribution of five top whole-genome association signals to hypertension in Han Chinese. J Hum Hypertens 2011; 25: 278–280.

    Article  Google Scholar 

  35. Loos RJ . Genetic determinants of common obesity and their value in prediction. Best Pract Res Clin Endocrinol Metab 2012; 26: 211–226.

    Article  CAS  Google Scholar 

  36. Ntzani EE, Kavvoura FK . Genetic risk factors for type 2 diabetes: insights from the emerging genomic evidence. Curr Vasc Pharmacol 2012; 10: 147–155.

    Article  CAS  Google Scholar 

  37. Delles C, Padmanabhan S . Genetics and hypertension: is it time to change my practice? Can J Cardiol 2012; 28: 296–304.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by National ‘Twelfth Five-Year’ Plan for Science & Technology Support Program (2012BAI03B03), Beijing Health System Leading Talent Grant (2009-1-08) Beijing Key Science and Technology Program (D111100000611002), the Research Fund for the Doctoral Program of Higher Education of China (20120131120004) and the Foundation for Outstanding Young Scientist in Shandong Province (BS2011YY026).

Author contributions

JM, XW: conceived and designed the experiments. YS: performed the experiments. BX, YL, JO, YZ, GRC: analyzed the data. XZ, DH: contributed reagents/materials/analysis tools. BX: wrote the manuscript.

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Correspondence to J Mi.

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Xi, B., Shen, Y., Zhao, X. et al. Association of common variants in/near six genes (ATP2B1, CSK, MTHFR, CYP17A1, STK39 and FGF5) with blood pressure/hypertension risk in Chinese children. J Hum Hypertens 28, 32–36 (2014). https://doi.org/10.1038/jhh.2013.50

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