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Examination of the associations between m6A-associated single-nucleotide polymorphisms and blood pressure


N6-methyladenosine (m6A) has been shown to play critical roles in many biological processes and a variety of diseases. The aim of this study was to investigate the association between m6A-associated single-nucleotide polymorphisms (m6A-SNPs) and blood pressure (BP) in large-scale genome-wide association studies and to test whether m6A-SNPs are enriched among the SNPs that were associated with BP. Furthermore, gene expression analysis was performed to obtain additional evidence for the identified m6A-SNPs. We found 1236 m6A-SNPs that were nominally associated with BP, and 33 of them were significant genome wide. The proportion of m6A-SNPs with a P < 0.05 was significantly higher than that of non-m6A-SNPs. Using fgwas, we found that SNPs associated with diastolic BP (P < 5 × 10–8) were significantly enriched with m6A-SNPs (log 2 enrichment of 2.67, 95% confidence interval: [0.42, 3.68]). Approximately 10% of the BP-associated m6A SNPs were associated with coronary artery disease or stroke. Most of these m6A-SNPs were strongly associated with gene expression. We showed that rs56001051, rs9847953, rs197922, and rs740406 were associated with C1orf167 (P = 0.019), ZNF589 (P = 0.013), GOSR2 (P = 0.001), and DOT1L (P = 0.032) expression levels in peripheral blood mononuclear cells of 40 Chinese individuals, respectively. The present study identified many BP-associated m6A-SNPs and demonstrated their potential functionality. The results suggested that m6A might play important roles in BP regulation.

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  1. 1.

    Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;9455:217–23.

  2. 2.

    Kupper N, Willemsen G, Riese H, Posthuma D, Boomsma DI, de Geus EJ. Heritability of daytime ambulatory blood pressure in an extended twin design. Hypertension. 2005;1:80–5.

  3. 3.

    Ehret GB, Ferreira T, Chasman DI, Jackson AU, Schmidt EM, Johnson T, et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet. 2016;10:1171–84.

  4. 4.

    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;7367:103–9.

  5. 5.

    Evangelou E, Warren HR, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet. 2018;10:1412–25.

  6. 6.

    Liu C, Kraja AT, Smith JA, Brody JA, Franceschini N, Bis JC, et al. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat Genet. 2016;10:1162–70.

  7. 7.

    Surendran P, Drenos F, Young R, Warren H, Cook JP, Manning AK, et al. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nat Genet. 2016;10:1151–61.

  8. 8.

    Yu B, Pulit SL, Hwang SJ, Brody JA, Amin N, Auer PL, et al. Rare exome sequence variants in CLCN6 reduce blood pressure levels and hypertension risk. Circ Cardiovasc Genet. 2016;1:64–70.

  9. 9.

    Mao F, Xiao L, Li X, Liang J, Teng H, Cai W, et al. RBP-Var: a database of functional variants involved in regulation mediated by RNA-binding proteins. Nucleic Acids Res. 2016;D1:D154–63.

  10. 10.

    Wu X, Hurst LD. Determinants of the usage of splice-associated cis-motifs predict the distribution of human pathogenic SNPs. Mol Biol Evol. 2016;2:518–29.

  11. 11.

    Ramaswami G, Deng P, Zhang R, Anna Carbone M, Mackay TF, Li JB. Genetic mapping uncovers cis-regulatory landscape of RNA editing. Nat Commun. 2015;6:8194.

  12. 12.

    Meyer KD, Jaffrey SR. The dynamic epitranscriptome: N 6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol. 2014;5:313–26.

  13. 13.

    Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N 6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;7481:117–20.

  14. 14.

    Edupuganti RR, Geiger S, Lindeboom RGH, Shi H, Hsu PJ, Lu Z, et al. N(6)-methyladenosine (m(6)A) recruits and repels proteins to regulate mRNA homeostasis. Nat Struct Mol Biol. 2017;10:870–8.

  15. 15.

    Visvanathan A, Somasundaram K. mRNA traffic control reviewed: N 6-methyladenosine (m(6) A) takes the driver’s seat. BioEssays. 2017;1:1700093.

  16. 16.

    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;D1:D139–45.

  17. 17.

    Kraja AT, Cook JP, Warren HR, Surendran P, Liu C, Evangelou E, et al. New blood pressure-associated loci identified in meta-analyses of 475 000 individuals. Circ Cardiovasc Genet. 2017;10: e001778.

  18. 18.

    Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;3:e1001779.

  19. 19.

    Pickrell JK. Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am J Hum Genet. 2014;4:559–73.

  20. 20.

    Liu Z, Qi H, Liu B, Liu K, Wu J, Cao H, et al. Genetic susceptibility to salt-sensitive hypertension in a Han Chinese population: a validation study of candidate genes. Hypertens Res. 2017;10:876–84.

  21. 21.

    Yang HC, Liang YJ, Chen JW, Chiang KM, Chung CM, Ho HY, et al. Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes in Han Chinese with a genome-wide gene-based association study. PLoS ONE. 2012;3:e32907.

  22. 22.

    Kelly TN, Takeuchi F, Tabara Y, Edwards TL, Kim YJ, Chen P, et al. Genome-wide association study meta-analysis reveals transethnic replication of mean arterial and pulse pressure loci. Hypertension. 2013;5:853–9.

  23. 23.

    Lu X, Wang L, Lin X, Huang J, Charles Gu C, He M, et al. Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension. Hum Mol Genet. 2015;24:865–74.

  24. 24.

    Nikpay M, Goel A, Won HH, Hall LM, Willenborg C, Kanoni S, et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet. 2015;10:1121–30.

  25. 25.

    Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;4:524–37.

  26. 26.

    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:D930–34.

  27. 27.

    Visvanathan A, Somasundaram K. mRNA traffic control reviewed: N 6-methyladenosine (m(6) A) takes the driver’s seat. BioEssays . 2018;1:1700093.

  28. 28.

    Shastry BS. SNPs: impact on gene function and phenotype. Methods Mol Biol. 2009;578:3–22.

  29. 29.

    Venturini L, Stadler M, Manukjan G, Scherr M, Schlegelberger B, Steinemann D, et al. The stem cell zinc finger 1 (SZF1)/ZNF589 protein has a human-specific evolutionary nucleotide DNA change and acts as a regulator of cell viability in the hematopoietic system. Exp Hematol. 2016;4:257–68.

  30. 30.

    Meyer TE, Shiffman D, Morrison AC, Rowland CM, Louie JZ, Bare LA, et al. GOSR2 Lys67Arg is associated with hypertension in whites. Am J Hypertens. 2009;2:163–8.

  31. 31.

    Bengtsson K, Melander O, Orho-Melander M, Lindblad U, Ranstam J, Rastam L, et al. Polymorphism in the beta(1)-adrenergic receptor gene and hypertension. Circulation. 2001;2:187–90.

  32. 32.

    Kong H, Li X, Zhang S, Guo S, Niu W. The beta1-adrenoreceptor gene Arg389Gly and Ser49Gly polymorphisms and hypertension: a meta-analysis. Mol Biol Rep. 2013;6:4047–53.

  33. 33.

    Wang H, Liu J, Liu K, Liu Y, Wang Z, Lou Y, et al. beta1-adrenoceptor gene Arg389Gly polymorphism and essential hypertension risk in general population: a meta-analysis. Mol Biol Rep. 2013;6:4055–63.

  34. 34.

    Wu D, Li G, Deng M, Song W, Huang X, Guo X, et al. Associations between ADRB1 and CYP2D6 gene polymorphisms and the response to beta-blocker therapy in hypertension. J Int Med Res. 2015;3:424–34.

  35. 35.

    Iulianella A, Sharma M, Durnin M, Vanden Heuvel GB, Trainor PA. Cux2 (Cutl2) integrates neural progenitor development with cell-cycle progression during spinal cord neurogenesis. Development. 2008;4:729–41.

  36. 36.

    Huang J, Ellinghaus D, Franke A, Howie B, Li Y. 1000 Genomes-based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium Phase 1 Data. Eur J Hum Genet. 2012;7:801–5.

  37. 37.

    Lee JY, Lee BS, Shin DJ, Woo Park K, Shin YA, Joong Kim K, et al. A genome-wide association study of a coronary artery disease risk variant. J Hum Genet. 2013;3:120–6.

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The study was supported by the Natural Science Foundation of China (81773508, 81673263), the Key Research Project (Social Development Plan) of Jiangsu Province (BE2016667), the Startup Fund from Soochow University (Q413900313, Q413900412), and a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Correspondence to Huan Zhang.

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  • Blood pressure
  • m6A
  • Methylation
  • Genome-wide association study
  • Gene expression
Fig. 1