Heart and Vessels

, Volume 34, Issue 1, pp 151–158 | Cite as

Functional promoter −1816C>G variant of RANKL predicts risk and prognosis of lone atrial fibrillation

  • Hailong Cao
  • Wei Xu
  • Xin Chen
  • Qing Zhou
  • Rongfang Lan
  • Yijiang Chen
  • Dongjin WangEmail author
Original Article


Receptor activator of nuclear factor-κB ligand (RANKL) had been confirmed contributing to the development and progression of AF by regulating atrial structural remodeling. But the involved genetic mechanism is unknown. We intended to explore the association between the polymorphism RANKL −1816C>G (rs7984870) and susceptibility and prognosis of lone AF. RANKL rs7984870 was genotyped in a case–control study of 828 patients and 834 controls in Chinese population. The CG and/or CC genotypes had an increased lone AF risk [adjusted odds ratio (OR) 1.20 for CG, OR 2.16 for CC, and OR 1.55 for CG/CC], compared with the GG genotype. Moreover, patients carrying CG/CC genotypes showed a higher possibility of AF recurrence after catheter ablation, compared with patients carrying GG genotype. In a genotype–phenotype correlation analysis using 24 normal left atrial appendage samples, increasing gradients of atrial RANKL expression levels positively correlated with atrial collagen volume fraction were identified in samples with CC, CG and GG genotypes. The in vitro luciferase assays also showed a higher luciferase activity of the −1816 C/C allele than that of the −1816 G/G allele. These results suggested that RANKL rs7984870 is involved in the etiology of lone AF and thus may be a marker for genetic susceptibility to lone AF and predicting prognosis after catheter ablation in Chinese populations. Therefore, we provide new information about treatment strategies and our understanding of RANKL in AF.


Receptor activator of nuclear factor-κB ligand Lone atrial fibrillation Genetic variation Susceptibility Prognosis 



The authors thank Dr. Ruyang Zhang (Department of Biostatistics, Nanjing Medical University, Nanjing, China) for his statistical assistance.


This work was supported in part by Jiangsu Provincial Medical Youth Talent [QNRC2016034], Jiangsu Province Health Department Program Grant [Z201411], Key Project supported by Medical Science and technology development Foundation, Nanjing Department of Health [JQX14006 and YKK17066].

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to disclose.


  1. 1.
    Lau DH, Nattel S, Kalman JM, Sanders P (2017) Modifiable risk factors and atrial fibrillation. Circulation 136:583–596CrossRefGoogle Scholar
  2. 2.
    Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A (1997) Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 96:1180–1184CrossRefGoogle Scholar
  3. 3.
    Mujovic NM, Marinkovic MM, Potpara TS, Geller L (2015) Catheter ablation of lone atrial fibrillation. Curr Pharm Des 21:591–612CrossRefGoogle Scholar
  4. 4.
    Cao H, Xue L, Xu X, Wu Y, Zhu J, Chen L, Chen D, Chen Y (2011) Heat shock proteins in stabilization of spontaneously restored sinus rhythm in permanent atrial fibrillation patients after mitral valve surgery. Cell Stress Chaperones 16:517–528CrossRefGoogle Scholar
  5. 5.
    Cao H, Li Q, Li M, Od R, Wu Z, Zhou Q, Cao B, Chen B, Chen Y, Wang D (2013) Osteoprotegerin/RANK/RANKL axis and atrial remodeling in mitral valvular patients with atrial fibrillation. Int J Cardiol 166:702–708CrossRefGoogle Scholar
  6. 6.
    Xi L, Cao H, Zhu J, Røe OD, Li M, Wu Y, Wang D, Chen Y (2013) OPG/RANK/RANKL axis in stabilization of spontaneously restored sinus rhythm in permanent atrial fibrillation patients after mitral valve surgery. Cardiology 124:18–24CrossRefGoogle Scholar
  7. 7.
    Spierings DC, de Vries EG, Vellenga E, van den Heuvel FA, Koornstra JJ, Wesseling J, Hollema H, de Jong S (2004) Tissue distribution of the death ligand TRAIL and its receptors. J Histochem Cytochem 52:821–831CrossRefGoogle Scholar
  8. 8.
    Cao H, Wang J, Xi L, Røe OD, Chen Y, Wang D (2011) Dysregulated atrial gene expression of osteoprotegerin/receptor activator of nuclear factor-κB (RANK)/RANK ligand axis in the development and progression of atrial fibrillation. Circ J 75:2781–2788CrossRefGoogle Scholar
  9. 9.
    Ueland T, Yndestad A, Oie E, Florholmen G, Halvorsen B, Froland SS, Simonsen S, Christensen G, Gullestad L, Aukrust P (2005) Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Circulation 111:2461–2468CrossRefGoogle Scholar
  10. 10.
    Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL (2000) The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15:2–12CrossRefGoogle Scholar
  11. 11.
    Tan W, Wu H, Zhao J, Derber LA, Lee DM, Shadick NA, Conn DL, Smith EA, Gersuk VH, Nepom GT, Moreland LW, Furst DE, Thompson SD, Jonas BL, Holers VM, Glass DN, Chen PP, Bridges SL Jr, Weinblatt ME, Paulus HE, Tsao BP (2010) A functional RANKL polymorphism associated with younger age at onset of rheumatoid arthritis. Arthritis Rheum 62:2864–2875CrossRefGoogle Scholar
  12. 12.
    Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J (2005) Association of osteoprotegerin with human abdominal aortic aneurysm progression. Circulation 111:3119–3125CrossRefGoogle Scholar
  13. 13.
    Cao H, Wu Y, Li Q, Wu Y, Zhou Q, Røe OD, Chen Y, Wang R, Wang D (2014) Serum sRANKL/OPG predict recurrence after radiofrequency catheter ablation of lone atrial fibrillation. Int J Cardiol 170:298–302CrossRefGoogle Scholar
  14. 14.
    Xu J, Cui G, Esmailian F, Plunkett M, Marelli D, Ardehali A, Odim J, Laks H, Sen L (2004) Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation. Circulation 109:363–368CrossRefGoogle Scholar
  15. 15.
    Spinale FG (2002) Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 90:520–530CrossRefGoogle Scholar
  16. 16.
    Yan AT, Yan RT, Spinale FG, Afzal R, Gunasinghe HR, Stroud RE, McKelvie RS, Liu PP (2008) Relationships between plasma levels of matrix metalloproteinases and neurohormonal profile in patients with heart failure. Eur J Heart Fail 10:125–128CrossRefGoogle Scholar
  17. 17.
    Rhee EJ, Oh KW, Jung CH, Lee WY, Oh ES, Yun EJ, Baek KH, Kang MI, Kim SW (2006) The relationship between four single nucleotide polymorphisms in the promoter region of the osteoprotegerin gene and aortic calcification or coronary artery disease in Koreans. Clin Endocrinol (Oxf) 64:689–697CrossRefGoogle Scholar
  18. 18.
    Sun T, Gao Y, Tan W, Ma S, Shi Y, Yao J, Guo Y, Yang M, Zhang X, Zhang Q, Zeng C, Lin D (2007) A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet 39:605–613CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Hailong Cao
    • 1
  • Wei Xu
    • 2
  • Xin Chen
    • 2
  • Qing Zhou
    • 1
  • Rongfang Lan
    • 2
  • Yijiang Chen
    • 3
  • Dongjin Wang
    • 1
    Email author
  1. 1.Department of Thoracic and Cardiovascular Surgerythe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
  2. 2.Department of Cardiologythe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
  3. 3.Department of Thoracic and Cardiovascular Surgerythe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina

Personalised recommendations