Genetic variants in CCNB1 associated with differential gene transcription and risk of coronary in-stent restenosis

Carlos Silvestre-Roig, Patricia Fernández, María L. Mansego, Claudia M. Van Tiel, Rosa Viana, Chiara Viviani Anselmi, Gianluigi Condorelli, Robbert J. De Winter, Paula Martín-Fuentes, María Solanas-Barca, Fernando Civeira, Amelia Focaccio, Carlie J M De Vries, Felipe Javier Chaves, Vicente Andrés

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 highrisk 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. Methods and 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.

Original languageEnglish
Pages (from-to)59-70
Number of pages12
JournalCirculation: Cardiovascular Genetics
Volume7
Issue number1
DOIs
Publication statusPublished - 2014

Fingerprint

Stents
Odds Ratio
Confidence Intervals
Genes
Single Nucleotide Polymorphism
Alleles
Cyclin B1
Drug-Eluting Stents
Transcription Factor AP-1
Reporter Genes
Angioplasty
Haplotypes
Cohort Studies
Transcription Factors
Cell Proliferation
Lymphocytes
Safety
Gene Expression
Costs and Cost Analysis
Messenger RNA

Keywords

  • AP-1 transcription factor
  • In-stent restenosis
  • NF-Y transcription factor
  • Polymorphism genetics
  • SP1 transcription factor
  • Stents

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Genetic variants in CCNB1 associated with differential gene transcription and risk of coronary in-stent restenosis. / Silvestre-Roig, Carlos; Fernández, Patricia; Mansego, María L.; Van Tiel, Claudia M.; Viana, Rosa; Anselmi, Chiara Viviani; Condorelli, Gianluigi; De Winter, Robbert J.; Martín-Fuentes, Paula; Solanas-Barca, María; Civeira, Fernando; Focaccio, Amelia; De Vries, Carlie J M; Chaves, Felipe Javier; Andrés, Vicente.

In: Circulation: Cardiovascular Genetics, Vol. 7, No. 1, 2014, p. 59-70.

Research output: Contribution to journalArticle

Silvestre-Roig, C, Fernández, P, Mansego, ML, Van Tiel, CM, Viana, R, Anselmi, CV, Condorelli, G, De Winter, RJ, Martín-Fuentes, P, Solanas-Barca, M, Civeira, F, Focaccio, A, De Vries, CJM, Chaves, FJ & Andrés, V 2014, 'Genetic variants in CCNB1 associated with differential gene transcription and risk of coronary in-stent restenosis', Circulation: Cardiovascular Genetics, vol. 7, no. 1, pp. 59-70. https://doi.org/10.1161/CIRCGENETICS.113.000305
Silvestre-Roig, Carlos ; Fernández, Patricia ; Mansego, María L. ; Van Tiel, Claudia M. ; Viana, Rosa ; Anselmi, Chiara Viviani ; Condorelli, Gianluigi ; De Winter, Robbert J. ; Martín-Fuentes, Paula ; Solanas-Barca, María ; Civeira, Fernando ; Focaccio, Amelia ; De Vries, Carlie J M ; Chaves, Felipe Javier ; Andrés, Vicente. / Genetic variants in CCNB1 associated with differential gene transcription and risk of coronary in-stent restenosis. In: Circulation: Cardiovascular Genetics. 2014 ; Vol. 7, No. 1. pp. 59-70.
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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 highrisk 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. Methods and 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.",
keywords = "AP-1 transcription factor, In-stent restenosis, NF-Y transcription factor, Polymorphism genetics, SP1 transcription factor, Stents",
author = "Carlos Silvestre-Roig and Patricia Fern{\'a}ndez and Mansego, {Mar{\'i}a L.} and {Van Tiel}, {Claudia M.} and Rosa Viana and Anselmi, {Chiara Viviani} and Gianluigi Condorelli and {De Winter}, {Robbert J.} and Paula Mart{\'i}n-Fuentes and Mar{\'i}a Solanas-Barca and Fernando Civeira and Amelia Focaccio and {De Vries}, {Carlie J M} and Chaves, {Felipe Javier} and Vicente Andr{\'e}s",
year = "2014",
doi = "10.1161/CIRCGENETICS.113.000305",
language = "English",
volume = "7",
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TY - JOUR

T1 - Genetic variants in CCNB1 associated with differential gene transcription and risk of coronary in-stent restenosis

AU - Silvestre-Roig, Carlos

AU - Fernández, Patricia

AU - Mansego, María L.

AU - Van Tiel, Claudia M.

AU - Viana, Rosa

AU - Anselmi, Chiara Viviani

AU - Condorelli, Gianluigi

AU - De Winter, Robbert J.

AU - Martín-Fuentes, Paula

AU - Solanas-Barca, María

AU - Civeira, Fernando

AU - Focaccio, Amelia

AU - De Vries, Carlie J M

AU - Chaves, Felipe Javier

AU - Andrés, Vicente

PY - 2014

Y1 - 2014

N2 - 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 highrisk 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. Methods and 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.

AB - 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 highrisk 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. Methods and 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.

KW - AP-1 transcription factor

KW - In-stent restenosis

KW - NF-Y transcription factor

KW - Polymorphism genetics

KW - SP1 transcription factor

KW - Stents

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