Research Paper Volume 12, Issue 13 pp 13076—13089

CircFOXO3 rs12196996, a polymorphism at the gene flanking intron, is associated with circFOXO3 levels and the risk of coronary artery disease

Yu-Lan Zhou1,2, , Wei-Peng Wu1, , Jie Cheng1, , Li-Li Liang1, , Jin-Ming Cen3, , Can Chen4, , Xinguang Liu1,5, , Xing-Dong Xiong1,5, ,

  • 1 Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, P.R. China
  • 2 Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, P.R. China
  • 3 Department of Cardiovascular Disease, The First People’s Hospital of Foshan, Foshan 528000, P.R. China
  • 4 Department of Cardiovascular Disease, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, P.R. China
  • 5 Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524001, P.R. China

Received: January 9, 2020       Accepted: May 25, 2020       Published: July 2, 2020
How to Cite

Copyright © 2020 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


CircFOXO3 plays an important role in the pathogenesis of coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) at circRNA flanking introns may change its back-splicing and influence circRNA formation. Here, we aimed to investigate the influence of the polymorphisms at the circFOXO3 flanking introns on individual susceptibility to CAD. A total of 1185 individuals were included in the case-control study. In a multivariate logistic regression analysis, we determined that the rs12196996 G variant was significantly associated with increased CAD risk (OR = 1.36, P = 0.014). A similar trend of the association was observed in the recessive model (OR = 2.57, P = 0.003). Stratified analysis revealed a more significant association with CAD risk among younger subjects and non-smokers. Consistent with these results, the haplotype rs12196996G-rs9398171C containing rs12196996G allele was also associated with increased CAD risk (OR = 1.31, P = 0.013). Further investigation revealed that the rs12196996 GG genotype was associated with decreased circFOXO3 expression, but not linear FOXO3 levels. Taken together, our data provide the first evidence that the rs12196996 polymorphism at the circFOXO3 gene flanking intron is associated with CAD risk in the Chinese Han population, which is probably due to influence circFOXO3 levels.


CAD: coronary artery disease; PCR-LDR: polymerase chain reaction-ligase detection reaction; FOXO3: forkhead box O3; CircFOXO3: circular RNA FOXO3; PBMC: peripheral blood mononuclear cell; OR: odds ratio; CI: confidence interval; SNP: single nucleotide polymorphism; SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglyceride; HDLC: high-density lipoprotein cholesterol; LDLC: low-density lipoprotein cholesterol; FPG: fasting plasma glucose; MAF: minor allele frequencies; SD: standard deviation; LD: linkage disequilibrium; GWAS: genome-wide association studies; circQTLs: circRNA quantitative trait loci; eQTLs: expression quantitative trait loci.