title: Genetic variants in CCNB1 associated with differential gene transcription and risk of coronary in-stent restenosis.
abstract: BACKGROUND
  The development of diagnostic tools to assess restenosis risk after stent deployment may enable the intervention to be tailored to the individual patient, for example, by targeting the use of drug-eluting stent to high-risk patients, with the goal of improving safety and reducing costs. The CCNB1 gene (encoding cyclin B1) positively regulates cell proliferation, a key component of in-stent restenosis. Therefore, we hypothesized that single-nucleotide polymorphisms in CCNB1 may serve as useful tools in risk stratification for in-stent restenosis.
  
  
  RESULTS
  We identified 3 single-nucleotide polymorphisms in CCNB1 associated with increased restenosis risk in a cohort of 284 patients undergoing coronary angioplasty and stent placement (rs350099: TT versus CC+TC; odds ratio [OR], 1.82; 95% confidence interval [CI], 1.09-3.03; P=0.023; rs350104: CC versus CT+TT; OR, 1.82; 95% CI, 1.02-3.26; P=0.040; and rs164390: GG versus GT+TT; OR, 2.27; 95% CI, 1.33-3.85; P=0.002). These findings were replicated in another cohort study of 715 patients (rs350099: TT versus CC+TC; OR, 1.88; 95% CI, 0.92-3.81; P=0.080; rs350104: CC versus CT+TT; OR, 2.23; 95% CI, 1.18-4.25; P=0.016; and rs164390: GG versus GT+TT; OR, 1.87; 95% CI, 1.03-3.47; P=0.040). Moreover, the haplotype containing all 3 risk alleles is associated with higher CCNB1 mRNA expression in circulating lymphocytes and increased in-stent restenosis risk (OR, 1.43; 95% CI, 1.00-1.823; P=0.039). The risk variants of rs350099, rs350104, and rs164390 are associated with increased reporter gene expression through binding of transcription factors nuclear factor-Y, activator protein 1, and specificity protein 1, respectively.
  
  
  CONCLUSIONS
  Allele-dependent transcriptional regulation of CCNB1 associated with rs350099, rs350104, and rs164390 affects the risk of in-stent restenosis. These findings reveal these common genetic variations as attractive diagnostic tools in risk stratification for restenosis.
authors.forename: Carlos
authors.initials: C
authors.lastname: Silvestre-Roig
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández
authors.forename: María L
authors.initials: ML
authors.lastname: Mansego
authors.forename: Claudia M
authors.initials: CM
authors.lastname: van Tiel
authors.forename: Rosa
authors.initials: R
authors.lastname: Viana
authors.forename: Chiara Viviani
authors.initials: CV
authors.lastname: Anselmi
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: de Winter
authors.forename: Paula
authors.initials: P
authors.lastname: Martín-Fuentes
authors.forename: María
authors.initials: M
authors.lastname: Solanas-Barca
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
authors.forename: Amelia
authors.initials: A
authors.lastname: Focaccio
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
authors.forename: Felipe Javier
authors.initials: FJ
authors.lastname: Chaves
authors.forename: Vicente
authors.initials: V
authors.lastname: Andrés
mesh_terms: D000483:Alleles; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D056744:Cyclin B1 / Q000235:genetics* / Q000378:metabolism; D054855:Drug-Eluting Stents; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D053208:Kaplan-Meier Estimate; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D023081:CCAAT-Binding Factor; C534699:CCNB1 protein, human; D056744:Cyclin B1; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1
keywords: AP-1 transcription factor; NF–Y transcription factor; SP1 transcription factor; in-stent restenosis; polymorphism, genetics; stents