Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation

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Gene-gene interaction is assumed to be critical to the pathogenesis of human disease, but its contribution to human disease phenotype needs definitive documentation. Moreover, the underlying molecular mechanism for gene-gene interaction is unknown. Here we use atrial fibrillation (AF) as a model to demonstrate that gene-gene interaction plays an important role in disease pathogenesis. Only three of the ten AF loci identified by GWAS in European ancestry populations, including PITX2c, ZFHX3, and CAV1, were replicated in the Chinese population and thus selected for gene-gene interaction studies. We show that the PITX2c locus interacts with the ZHFX3 locus to increase the risk of AF. Because gene-gene interaction can generate synergistic effect that markedly increases risk of AF, we conclude that gene-gene interaction accounts for a significant portion of heritability of AF. Mechanistically, PITX2c positively regulates ZHFX3 via miR-1 and ZHFX3 positively regulates PITX2c, which generates a loop of cross-regulation of the two genes. Our study suggests that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interaction involved in disease phenotype.

Vyšlo v časopise: Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005393
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005393

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Zdroje

1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, et al. (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 285 : 2370–2375. 11343485

2. Hu D, Sun Y (2008) Epidemiology, risk factors for stroke, and management of atrial fibrillation in China. J Am Coll Cardiol 52 : 865–868. doi: 10.1016/j.jacc.2008.05.042 18755352

3. Fujii H, Kim JI, Yoshiya K, Nishi S, Fukagawa M (2011) Clinical characteristics and cardiovascular outcomes of hemodialysis patients with atrial fibrillation: a prospective follow-up study. Am J Nephrol 34 : 126–134. doi: 10.1159/000329118 21720157

4. Christophersen IE, Ravn LS, Budtz-Joergensen E, Skytthe A, Haunsoe S, et al. (2009) Familial aggregation of atrial fibrillation: a study in Danish twins. Circ Arrhythm Electrophysiol 2 : 378–383. doi: 10.1161/CIRCEP.108.786665 19808493

5. Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, et al. (2007) Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448 : 353–357. 17603472

6. Shi L, Li C, Wang C, Xia Y, Wu G, et al. (2009) Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Hum Genet 126 : 843–849. doi: 10.1007/s00439-009-0737-3 19707791

7. Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB, et al. (2009) A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 41 : 876–878. doi: 10.1038/ng.417 19597491

8. Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, et al. (2009) Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 41 : 879–881. doi: 10.1038/ng.416 19597492

9. Li C, Wang F, Yang Y, Fu F, Xu C, et al. (2011) Significant association of SNP rs2106261 in the ZFHX3 gene with atrial fibrillation in a Chinese Han GeneID population. Hum Genet 129 : 239–246. doi: 10.1007/s00439-010-0912-6 21107608

10. Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, et al. (2010) Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 42 : 240–244. doi: 10.1038/ng.537 20173747

11. Ellinor PT, Lunetta KL, Albert CM, Glazer NL, Ritchie MD, et al. (2012) Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 44 : 670–675. doi: 10.1038/ng.2261 22544366

12. Chen S, Wang C, Wang X, Xu C, Wu M, et al. (2015) Significant Association Between CAV1 Variant rs3807989 on 7p31 and Atrial Fibrillation in a Chinese Han Population. J Am Heart Assoc 4.

13. Wang J, Klysik E, Sood S, Johnson RL, Wehrens XH, et al. (2010) Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proc Natl Acad Sci U S A 107 : 9753–9758. doi: 10.1073/pnas.0912585107 20457925

14. Kirchhof P, Kahr PC, Kaese S, Piccini I, Vokshi I, et al. (2011) PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. Circ Cardiovasc Genet 4 : 123–133. doi: 10.1161/CIRCGENETICS.110.958058 21282332

15. Chinchilla A, Daimi H, Lozano-Velasco E, Dominguez JN, Caballero R, et al. (2011) PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circ Cardiovasc Genet 4 : 269–279. doi: 10.1161/CIRCGENETICS.110.958116 21511879

16. Ganga M, Espinoza HM, Cox CJ, Morton L, Hjalt TA, et al. (2003) PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5. J Biol Chem 278 : 22437–22445. 12692125

17. Hilton T, Gross MK, Kioussi C (2010) Pitx2-dependent occupancy by histone deacetylases is associated with T-box gene regulation in mammalian abdominal tissue. J Biol Chem 285 : 11129–11142. doi: 10.1074/jbc.M109.087429 20129917

18. Tao Y, Zhang M, Li L, Bai Y, Zhou Y, et al. (2014) Pitx2, an atrial fibrillation predisposition gene, directly regulates ion transport and intercalated disc genes. Circ Cardiovasc Genet 7 : 23–32. doi: 10.1161/CIRCGENETICS.113.000259 24395921

19. Zou GY (2008) On the estimation of additive interaction by use of the four-by-two table and beyond. Am J Epidemiol 168 : 212–224. doi: 10.1093/aje/kwn104 18511428

20. Cordell HJ, Clayton DG (2002) A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet 70 : 124–141. 11719900

21. Herold C, Steffens M, Brockschmidt FF, Baur MP, Becker T (2009) INTERSNP: genome-wide interaction analysis guided by a priori information. Bioinformatics 25 : 3275–3281. doi: 10.1093/bioinformatics/btp596 19837719

22. Ritchie MD, Rowan S, Kucera G, Stubblefield T, Blair M, et al. (2012) Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation. J Am Coll Cardiol 60 : 1173–1181. doi: 10.1016/j.jacc.2012.04.030 22818067

23. Lubitz SA, Lunetta KL, Lin H, Arking DE, Trompet S, et al. (2014) Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. J Am Coll Cardiol 63 : 1200–1210. doi: 10.1016/j.jacc.2013.12.015 24486271

24. Franco D, Campione M (2003) The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases. Trends Cardiovasc Med 13 : 157–163. 12732450

25. Faucourt M, Houliston E, Besnardeau L, Kimelman D, Lepage T (2001) The pitx2 homeobox protein is required early for endoderm formation and nodal signaling. Dev Biol 229 : 287–306. 11203696

26. Mommersteeg MT, Hoogaars WM, Prall OW, de Gier-de Vries C, Wiese C, et al. (2007) Molecular pathway for the localized formation of the sinoatrial node. Circ Res 100 : 354–362. 17234970

27. Yasuda H, Mizuno A, Tamaoki T, Morinaga T (1994) ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene. Mol Cell Biol 14 : 1395–1401. 7507206

28. Morinaga T, Yasuda H, Hashimoto T, Higashio K, Tamaoki T (1991) A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers. Mol Cell Biol 11 : 6041–6049. 1719379

29. Berry FB, Miura Y, Mihara K, Kaspar P, Sakata N, et al. (2001) Positive and negative regulation of myogenic differentiation of C2C12 cells by isoforms of the multiple homeodomain zinc finger transcription factor ATBF1. J Biol Chem 276 : 25057–25065. 11312261

30. Jung CG, Kim HJ, Kawaguchi M, Khanna KK, Hida H, et al. (2005) Homeotic factor ATBF1 induces the cell cycle arrest associated with neuronal differentiation. Development 132 : 5137–5145. 16251211

31. Ido A, Miura Y, Watanabe M, Sakai M, Inoue Y, et al. (1996) Cloning of the cDNA encoding the mouse ATBF1 transcription factor. Gene 168 : 227–231. 8654949

32. Wang F, Xu CQ, He Q, Cai JP, Li XC, et al. (2011) Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat Genet 43 : 345–349. doi: 10.1038/ng.783 21378986

33. Xu C, Wang F, Wang B, Li X, Li C, et al. (2010) Minor allele C of chromosome 1p32 single nucleotide polymorphism rs11206510 confers risk of ischemic stroke in the Chinese Han population. Stroke 41 : 1587–1592. doi: 10.1161/STROKEAHA.110.583096 20576952

34. Cheng X, Shi L, Nie S, Wang F, Li X, et al. (2011) The same chromosome 9p21.3 locus is associated with type 2 diabetes and coronary artery disease in a Chinese Han population. Diabetes 60 : 680–684. doi: 10.2337/db10-0185 21270277

35. Li X, Huang Y, Yin D, Wang D, Xu C, et al. (2013) Meta-analysis identifies robust association between SNP rs17465637 in MIA3 on chromosome 1q41 and coronary artery disease. Atherosclerosis 231 : 136–140. doi: 10.1016/j.atherosclerosis.2013.08.031 24125424

36. Xiong X, Xu C, Zhang Y, Li X, Wang B, et al. (2014) BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3. Hum Genet 133 : 499–508. doi: 10.1007/s00439-013-1389-x 24190014

37. Bai Y, Nie S, Jiang G, Zhou Y, Zhou M, et al. (2014) Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke. Stroke 45 : 383–388. doi: 10.1161/STROKEAHA.113.003393 24385277

38. Tu X, Nie S, Liao Y, Zhang H, Fan Q, et al. (2013) The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese Han population. Am J Hum Genet 93 : 652–660. doi: 10.1016/j.ajhg.2013.08.009 24075188

39. Ren X, Xu C, Zhan C, Yang Y, Shi L, et al. (2010) Identification of NPPA variants associated with atrial fibrillation in a Chinese GeneID population. Clin Chim Acta 411 : 481–485. doi: 10.1016/j.cca.2009.12.019 20064500

40. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, et al. (2006) ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 114: e257–354. 16908781

41. Oberti C, Wang L, Li L, Dong J, Rao S, et al. (2004) Genome-wide linkage scan identifies a novel genetic locus on chromosome 5p13 for neonatal atrial fibrillation associated with sudden death and variable cardiomyopathy. Circulation 110 : 3753–3759. 15596564

42. Zhang X, Chen S, Yoo S, Chakrabarti S, Zhang T, et al. (2008) Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell 135 : 1017–1027. doi: 10.1016/j.cell.2008.10.022 19070573

43. Zhou B, Ma R, Si W, Li S, Xu Y, et al. (2013) MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth. Cancer Lett 333 : 159–169. doi: 10.1016/j.canlet.2013.01.028 23352645

44. Xu Y, Zhou M, Wang J, Zhao Y, Li S, et al. (2014) Role of microRNA-27a in down-regulation of angiogenic factor AGGF1 under hypoxia associated with high-grade bladder urothelial carcinoma. Biochim Biophys Acta 1842 : 712–725. doi: 10.1016/j.bbadis.2014.01.007 24462738

45. Fan C, Liu M, Wang Q (2003) Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome. J Biol Chem 278 : 8780–8785. 12499378

46. Rothman KJ (1976) The estimation of synergy or antagonism. Am J Epidemiol 103 : 506–511. 1274952

47. Greenland S, Poole C (1988) Invariants and noninvariants in the concept of interdependent effects. Scand J Work Environ Health 14 : 125–129. 3387960

48. Wang X, Elston RC, Zhu X (2010) The meaning of interaction. Hum Hered 70 : 269–277. doi: 10.1159/000321967 21150212

49. Kalilani L, Atashili J (2006) Measuring additive interaction using odds ratios. Epidemiol Perspect Innov 3 : 5. 16620385