Genetic Variants in CCNB1 Associated with Differential Gene Transcription and Risk of Coronary In-Stent Restenosis

+Author Affiliations

¹Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain / Current Address: Department Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
²Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain / Current Address: National Cancer Institute, NIH, Bethesda, MD
³Genotyping and Genetic Diagnosis Unit, Fundación Investigación Clínico de Valencia-INCLIVA & CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Valencia, Spain
⁴Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
⁵Instituto de Biomedicina de Valencia (IBV-CSIC), Valencia, Spain
⁶Multimedica Research Hospital, Milan, Italy
⁷Humanitas Clinical and Research Center & University of Milan, Milan, Italy
⁸Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
⁹Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet (I+CS), Zaragoza, Spain
¹⁰Clinica Mediterranea, Naples, Italy
¹¹Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

↵* Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain vandres@cnic.es

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 drug-eluting stent's use 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 (ISR). We therefore hypothesized that single nucleotide polymorphisms (SNPs) in CCNB1 may serve as useful tools in risk stratification for ISR.

Methods and Results—We identified 3 SNPs in CCNB1 associated with increased restenosis risk in a cohort of 284 patients undergoing coronary angioplasty and stent placement (rs350099: TT vs. CC+TC, OR=1.82, 95%CI=1.09-3.03, p=0.023; rs350104: CC vs. CT+TT, OR=1.82, 95%CI=1.02-3.26, p=0.040; rs164390: GG vs. 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 vs. CC+TC, OR=1.88, 95%CI=0.92-3.81, p=0.080; rs350104: CC vs. CT+TT, OR=2.23, 95%CI=1.18-4.25, p=0.016; rs164390: GG vs. GT+TT, OR=1.87, 95%CI=1.03-3.47, p=0.040). Moreover, the haplotype containing all three risk alleles is associated with higherCCNB1 mRNA expression in circulating lymphocytes and increased ISR 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 NF-Y, AP-1 and SP1, respectively.

Conclusions—Allele-dependent transcriptional regulation of CCNB1 associated with rs350099, rs350104 and rs164390 affects the risk of ISR. These findings reveal these common genetic variations as attractive diagnostic tools in risk stratification for restenosis.

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