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Associations among NPPA gene polymorphisms, serum ANP levels, and hypertension in the Chinese Han population

Abstract

The natriuretic peptide system plays an important role in regulation of blood pressure. The purpose of this study was to comprehensively examine the associations among NPPA gene SNPs, serum atrial natriuretic peptide (ANP) levels, and hypertension. In 736 new-onset hypertensive cases and 736 age- and sex-matched controls, we measured concentrations of serum NT-proANP and genotyped 3 tag-SNPs in NPPA. Serum ANP levels were significantly lower in hypertensive patients than in controls (Wilcoxon two sample test P = 0.011). The difference was also significant in male (P = 0.0161) and female subgroups (P = 0.0011). Compared with the reference group, participants with the highest quartile of ANP levels had a significant decreased risk of hypertension (odds ratio = 0.56, P = 0.0006). The nonsynonymous SNP rs5063 (p.Val32Met) seemed to be associated with ANP levels (P = 0.0209). eQTL analysis found that rs198358 was associated with NPPA gene expression in testis (1.66 × 10−9) and whole blood (4.58 × 10−52). The findings suggested that a common NPPA SNPs rs5063 was associated with serum ANP levels and ANP was prospectively associated with hypertension in the Chinese Han population.

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References

  1. Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet. 2015;386:801–12.

    Article  Google Scholar 

  2. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–23.

    Article  Google Scholar 

  3. Lewington S, Lacey B, Clarke R, Guo Y, Kong XL, Yang L, et al. The burden of hypertension and associated risk for cardiovascular mortality in China. JAMA Intern Med. 2016;176:524–32.

    Article  Google Scholar 

  4. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med. 1998;339:321–8.

    Article  CAS  Google Scholar 

  5. Steinhelper ME, Cochrane KL, Field LJ. Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes. Hypertension. 1990;16:301–7.

    Article  CAS  Google Scholar 

  6. John SW, Krege JH, Oliver PM, Hagaman JR, Hodgin JB, Pang SC, et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science. 1995;267:679–81.

    Article  CAS  Google Scholar 

  7. Conen D, Cheng S, Steiner LL, Buring JE, Ridker PM, Zee RY. Association of 77 polymorphisms in 52 candidate genes with blood pressure progression and incident hypertension: the Women’s Genome Health Study. J Hypertens. 2009;27:476–83.

    Article  CAS  Google Scholar 

  8. Conen D, Glynn RJ, Buring JE, Ridker PM, Zee RY. Natriuretic peptide precursor a gene polymorphisms and risk of blood pressure progression and incident hypertension. Hypertension. 2007;50:1114–9.

    Article  CAS  Google Scholar 

  9. 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;41:666–76.

    Article  CAS  Google Scholar 

  10. Newton-Cheh C, Larson MG, Vasan RS, Levy D, Bloch KD, Surti A, et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet. 2009;41:348–53.

    Article  CAS  Google Scholar 

  11. Giri A, Hellwege JN, Keaton JM, Park J, Qiu C, Warren HR, et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat Genet. 2019;51:51–62.

    Article  CAS  Google Scholar 

  12. Salo PP, Havulinna AS, Tukiainen T, Raitakari O, Lehtimaki T, Kahonen M, et al. Genome-wide association study implicates atrial natriuretic peptide rather than B-type natriuretic peptide in the regulation of blood pressure in the general population. Circ Cardiovasc Genet. 2017;10:e001713.

    Article  CAS  Google Scholar 

  13. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.

    Article  CAS  Google Scholar 

  14. Zheng Y, Nie P, Peng D, He Z, Liu M, Xie Y, et al. m6AVar: a database of functional variants involved in m6A modification. Nucleic Acids Res. 2018;46:D139–45.

    Article  CAS  Google Scholar 

  15. Ren J, Jiang C, Gao X, Liu Z, Yuan Z, Jin C, et al. PhosSNP for systematic analysis of genetic polymorphisms that influence protein phosphorylation. Mol Cell Proteom. 2010;9:623–34.

    Article  CAS  Google Scholar 

  16. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–4.

    Article  CAS  Google Scholar 

  17. Kheradpour P, Kellis M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 2014;42:2976–87.

    Article  CAS  Google Scholar 

  18. Ryu GM, Song P, Kim KW, Oh KS, Park KJ, Kim JH. Genome-wide analysis to predict protein sequence variations that change phosphorylation sites or their corresponding kinases. Nucleic Acids Res. 2009;37:1297–307.

    Article  CAS  Google Scholar 

  19. Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol. 2009;191:341–66.

  20. Curry FR. Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume. J Clin Invest. 2005;115:1458–61.

    Article  CAS  Google Scholar 

  21. Song W, Wang H, Wu Q. Atrial natriuretic peptide in cardiovascular biology and disease (NPPA). Gene. 2015;569:1–6.

    Article  CAS  Google Scholar 

  22. Rubattu S, Bigatti G, Evangelista A, Lanzani C, Stanzione R, Zagato L, et al. Association of atrial natriuretic peptide and type a natriuretic peptide receptor gene polymorphisms with left ventricular mass in human essential hypertension. J Am Coll Cardiol. 2006;48:499–505.

    Article  CAS  Google Scholar 

  23. Arora P, Wu C, Khan AM, Bloch DB, Davis-Dusenbery BN, Ghorbani A, et al. Atrial natriuretic peptide is negatively regulated by microRNA-425. J Clin Invest. 2013;123:3378–82.

    Article  CAS  Google Scholar 

  24. Pereira NL, Tosakulwong N, Scott CG, Jenkins GD, Prodduturi N, Chai Y, et al. Circulating atrial natriuretic peptide genetic association study identifies a novel gene cluster associated with stroke in whites. Circ Cardiovasc Genet. 2015;8:141–9.

    Article  CAS  Google Scholar 

  25. Wang J, Wang Z, Yu C. Association of polymorphisms in the atrial natriuretic factor gene with the risk of essential hypertension: a systematic review and meta-analysis. Int J Environ Res Public Health. 2016;13:458.

    Article  Google Scholar 

  26. Jeong Y, Leskow FC, El-Jaick K, Roessler E, Muenke M, Yocum A, et al. Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat Genet. 2008;40:1348–53.

    Article  CAS  Google Scholar 

  27. Hammaker D, Whitaker JW, Maeshima K, Boyle DL, Ekwall AH, Wang W, et al. LBH gene transcription regulation by the interplay of an enhancer risk allele and DNA methylation in rheumatoid arthritis. Arthritis Rheuma. 2016;68:2637–45.

    Article  CAS  Google Scholar 

  28. Fogarty MP, Panhuis TM, Vadlamudi S, Buchkovich ML, Mohlke KL. Allele-specific transcriptional activity at type 2 diabetes-associated single nucleotide polymorphisms in regions of pancreatic islet open chromatin at the JAZF1 locus. Diabetes. 2013;62:1756–62.

    Article  CAS  Google Scholar 

  29. Nakatochi M, Ichihara S, Yamamoto K, Naruse K, Yokota S, Asano H, et al. Epigenome-wide association of myocardial infarction with DNA methylation sites at loci related to cardiovascular disease. Clin Epigenetics. 2017;9:54.

    Article  Google Scholar 

  30. Paneni F, Costantino S, Battista R, Castello L, Capretti G, Chiandotto S, et al. Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus. Circ Cardiovasc Genet. 2015;8:150–8.

    Article  CAS  Google Scholar 

  31. Liu Y, Peng W, Qu K, Lin X, Zeng Z, Chen J, et al. TET2: a novel epigenetic regulator and potential intervention target for atherosclerosis. DNA Cell Biol. 2018;37:517–23.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported by Natural Science Foundation of China (81773508, 81673263, 81302499, and 81320108026), the Key Research Project (Social Development Plan) of Jiangsu Province (BE2016667), Project funded by China Postdoctoral Science Foundation (2014T70547, 2013M530269, and 2014M551649), the Startup Fund from Soochow University (Q413900313 and Q413900412), and a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Zhang, H., Mo, X., Zhou, Z. et al. Associations among NPPA gene polymorphisms, serum ANP levels, and hypertension in the Chinese Han population. J Hum Hypertens 33, 641–647 (2019). https://doi.org/10.1038/s41371-019-0219-6

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