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The variants at FLNA and FLNB contribute to the susceptibility of hypertension and stroke with differentially expressed mRNA

The Pharmacogenomics Journal volume 21, pages 458–466 (2021)Cite this article

Subjects

Abstract

Background

Filamin A and filamin B were involved in vascular development and remodeling. Herein, it is important to explore the associations of FLNA and FLNB variants with hypertension and stroke.

Methods

The associations of two single-nucleotide polymorphisms (SNPs) at FLNA and five SNPs at FLNB with hypertension and stroke were examined in two case-control studies and a cohort study in Chinese Han population. Risks were estimated as odds ratio (OR) and hazard ratio (HR) by Logistic and Cox regression analysis respectively. In addition, filamin B, FLNA and FLNB mRNA expression were measured.

Results

In the case-control study of hypertension, FLNA rs2070816 (CT + TT vs. CC) and rs2070829 (CG + GG vs. CC) were significantly associated with hypertension in <55 years group (OR = 1.338, P = 0.018; OR = 1.615, P = 0.005) and FLNB rs839240 (AG + GG vs. AA) was significantly associated with hypertension in females (OR = 0.828, P = 0.041) and nonsmokers (OR = 0.829, P = 0.020). In the follow-up study, rs2070829 GG genotype carriers presented a higher risk of hypertension than CC/CG in males (HR = 1.737, P = 0.014) and smokers (HR = 1.949, P = 0.012). In the case-control study of stroke, FLNB rs1131356 variation was significantly associated with ischemic stroke (IS) and intracerebral hemorrhage (ICH), ORs of additive model were 1.342 and 1.451, with P values of 0.001 and 0.007. The FLNA transcript 2, FLNB transcript 3, transcript 4 mRNA, and filamin B expression levels were significantly different between IS cases and hypertension controls and among the genotypes of rs839240 in hypertensive individuals (P < 0.05).

Conclusions

Our findings support the genetic contribution of FLNA and FLNB to hypertension, and stroke with differentially mRNA expression.

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Fig. 1: Comparing of mRNA expression level between stroke cases and hypertension controls.
Fig. 2: Comparing of mRNA expression level of FLNB common transcript, FLNB transcript 3 and transcript 4 among the genotypes of rs839240.
Fig. 3: Comparing of plasma filamin B among IS cases, HT cases and controls.

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References

  1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation. 2017; 135: CIR.0000000000000485.

  2. Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in China: huge burden, significant workload, and a national priority. Stroke. 2011;42:3651–4.

    Article  Google Scholar 

  3. Zhou M, Wang H, Zhu J, Chen W, Wang L, Liu S, et al. Cause-specific mortality for 240 causes in China during 1990-2013: a systematic subnational analysis for the Global Burden of Disease Study 2013. Lancet. 2016;387:251–72.

    Article  Google Scholar 

  4. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, et al. Update on the global burden of ischemic and hemorrhagic stroke in 1990–2013: The GBD 2013 study. Neuroepidemiology. 2015;45:161–76.

    Article  Google Scholar 

  5. Yang S, Zhao Y, Chen X, Lu X, Chen Y, Zhao X, et al. The ACTB variants and alcohol drinking confer joint effect to ischemic stroke in Chinese Han population. J Atheroscler Thromb. 2020;27:226–44.

    Article  CAS  Google Scholar 

  6. O’Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016;388:761–75.

    Article  Google Scholar 

  7. Ibrahim J, McGee A, Graham D, McGrath JC, Dominiczak AF. Sex-specific differences in cerebral arterial myogenic tone in hypertensive and normotensive rats. Am J Physiol Heart Circ Physiol. 2006;290:H1081–1089.

    Article  CAS  Google Scholar 

  8. Legrand MC, Benessiano J, Levy BI. Endothelium, mechanical compliance, and cGMP content in the carotid artery from spontaneously hypertensive rats. J Cardiovasc Pharm. 1993;21 Suppl 1:S26–30.

    Article  Google Scholar 

  9. Cunningham CC, Stossel TP. Actin-binding protein requirement for cortical stability and efficient locomotion. Science. 1992;255:325–7.

    Article  CAS  Google Scholar 

  10. Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F, et al. Filamin A (FLNA) is required for cell–cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci. 2006;103:19836–41.

    Article  CAS  Google Scholar 

  11. Gorlin JB, Yamin R, Egan S, Stewart M, Stossel TP, Kwiatkowski DJ, et al. Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring. J Cell Biol. 1990;111:1089–105.

    Article  CAS  Google Scholar 

  12. Weihing RR. Actin-binding and dimerization domains of HeLa cell filamin. Biochemistry. 1988;27:1865.

    Article  CAS  Google Scholar 

  13. Bellanger JM, Astier C, Sardet C, Ohta Y, Stossel TP, Debant A. The Rac1- and RhoG-specific GEF domain of Trio targets filamin to remodel cytoskeletal actin. Nat Cell Biol. 2000;2:888–92.

    Article  CAS  Google Scholar 

  14. Kim H, Sengupta A, Glogauer M, McCulloch CA. Filamin A regulates cell spreading and survival via beta1 integrins. Exp Cell Res. 2008;314:834–46.

    Article  CAS  Google Scholar 

  15. Ueda K, Ohta Y, Hosoya H. The carboxy-terminal pleckstrin homology domain of ROCK interacts with filamin-A. Biochem Biophys Res Commun. 2003;301:886–90.

    Article  CAS  Google Scholar 

  16. Sasaki A, Masuda Y, Ohta Y, Ikeda K, Watanabe K. Filamin associates with Smads and regulates transforming growth factor-beta signaling. J Biol Chem. 2001;276:17871–7.

    Article  CAS  Google Scholar 

  17. Zacchigna L, Vecchione C, Notte A, Cordenonsi M, Dupont S, Maretto S, et al. Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell. 2006;124:929–42.

    Article  CAS  Google Scholar 

  18. Hart AW, Morgan JE, Schneider J, West K, Mckie L, Bhattacharya S, et al. Cardiac malformations and midline skeletal defects in mice lacking filamin A. Hum Mol Genet. 2006;15:2457–67.

    Article  CAS  Google Scholar 

  19. Reinstein E, Frentz S, Morgan T, Leventer RJ, Mcgillivray G, Pariani M, et al. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. Eur J Hum Genet. 2013;21:494–502.

    Article  CAS  Google Scholar 

  20. Zhou X, Borén J, Akyürek LM. Filamins in cardiovascular development. Trends Cardiovascular Med. 2007;17:222–9.

    Article  CAS  Google Scholar 

  21. Sheen VL, Feng Y, Graham D, Takafuta T, Shapiro SS, Walsh CA, et al. and Filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact. Hum Mol Genet. 2002;11:2845–54.

    Article  CAS  Google Scholar 

  22. Latta RJ, Graham CB, Aase J, Scham SM, Smith DW. Larsen’s syndrome: a skeletal dysplasia with multiple joint dislocations and unusual facies. J Pediatr. 1971;78:291–8.

    Article  CAS  Google Scholar 

  23. Zhou X, Tian F, Sandzen J, Cao R, Flaberg E, Szekely L, et al. Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development. Proc Natl Acad Sci USA. 2007;104:3919–24.

    Article  CAS  Google Scholar 

  24. Steiner CE, Torriani M, Norato DY, Marquesdefaria AP. Spondylocarpotarsal synostosis with ocular findings. Am J Med Genet Part A. 2000;91:131–4.

    Article  CAS  Google Scholar 

  25. Yang S, Chen Y, Liu C, Zhao X, Zhuang Q, Sun J, et al. Association study of common variants in PFN1 with hypertension in a Han Chinese population: a case-control study and a follow-up study. Am J Hypertens. 2017;30:1024–31.

    Article  CAS  Google Scholar 

  26. Huelsmann S, Rintanen N, Sethi R, Brown NH, Ylanne J. Evidence for the mechanosensor function of filamin in tissue development. Sci Rep. 2016;6:32798.

    Article  CAS  Google Scholar 

  27. Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003;33:487–91.

    Article  CAS  Google Scholar 

  28. Feng Y, Walsh CA. The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol. 2004;6:1034–8.

    Article  CAS  Google Scholar 

  29. Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F, et al. Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci USA. 2006;103:19836–41.

    Article  CAS  Google Scholar 

  30. Robertson SP, Filamin A. Phenotypic diversity. Curr Opin Genet Devolopment. 2005;15:301–7.

    Article  CAS  Google Scholar 

  31. Guerrini R, Mei D, Sisodiya S, Sicca F, Harding B, Takahashi Y, et al. Germline and mosaic mutations of FLN1 in men with periventricular heterotopia. Neurology. 2004;63:51–56.

    Article  CAS  Google Scholar 

  32. Kochar MS, Bindra RS. The additive effects of smoking and hypertension. More reasons to help your patients kick the habit. Postgrad Med. 1996;100:147–8. 151-144, 159-160

    Article  CAS  Google Scholar 

  33. Lu J, Lian G, Lenkinski R, De Grand A, Vaid RR, Bryce T, et al. Filamin B mutations cause chondrocyte defects in skeletal development. Hum Mol Genet. 2007;16:1661–75.

    Article  CAS  Google Scholar 

  34. Bicknell LS, Farrington-Rock C, Shafeghati Y, Rump P, Alanay Y, Alembik Y, et al. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet. 2007;44:89–98.

    Article  CAS  Google Scholar 

  35. Krakow D, Robertson SP, King LM, Morgan T, Sebald ET, Bertolotto C, et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet. 2004;36:405–10.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81573232 and No. 81872686), Jiangsu Provincial Fourth “333 Project”, the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine) and the Flagship Major Development of Jiangsu Higher Education Institutions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: C Liu, W Tang, H Zhao

Authors and Affiliations

  1. Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China

    Chunlan Liu, Hailong Zhao & Chong Shen

  2. Department of Neurology, Affiliated Yixing People’s Hospital of Jiangsu University, People’s Hospital of Yixing City, Yixing, China

    Wuzhuang Tang, Zhanyun Ren, Jie Li, Donghua Xu & Yanping Zhao

  3. Department of Cardiology, Affiliated Yixing People’s Hospital of Jiangsu University, People’s Hospital of Yixing City, Yixing, China

    Song Yang, Yanchun Chen & Xianghai Zhao

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  1. Chunlan Liu
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Liu, C., Tang, W., Zhao, H. et al. The variants at FLNA and FLNB contribute to the susceptibility of hypertension and stroke with differentially expressed mRNA. Pharmacogenomics J 21, 458–466 (2021). https://doi.org/10.1038/s41397-021-00222-y

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