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. The incidence of restenosis is highly influenced by clinical, biological, and procedural and lesion-related risk factors. 4 However, information on restenosis biomarkers is scarce. Single-nucleotide polymorphisms (SNPs) are recognized as suitable markers of disease predisposition. Methods and Results-We5 SNPs in the human genome occur on average once every 300 nucleotides (≈10 million SNPs), making them the most common type of genetic variation. SNPs reported to influence restenosis risk affect platelet activation, leukocyte recruitment, the inflammatory response, metalloproteinases, lipid metabolism, oxidative stress, nitric oxide, the renin-angiotensin system, and cell proliferation. 4,6,7 Interestingly, the 838C>A SNP in CDKN1B (encoding the tumor suppressor p27 Kip1 ) has been associated with restenosis risk after coronary stenting, which might be because of augmented vascular smooth muscle cell proliferation caused by reduced CDKN1B promoter activity in patients carrying the risk allele.8 However, other SNPs in CDKN1B or TP53 (encoding the tumor suppressor p53) showed lack of association with restenosis risk. 8,9 In the present study, we investigated a potential association of restenosis risk with SNPs in the CCNB1 gene (encoding cyclin B1). Cyclin B1 is essential for cell proliferation, and its ablation in the mouse is embryonically lethal.10 Several regulatory mechanisms are necessary to ensure that cyclin B1 protein accumulates appreciably only during the G2/M cell cycle transition, and deregulated CCNB1 transcription leading to aberrantly high levels of cyclin B1 throughout the cell cycle is associated with excessive hyperplasia in several human cancers.11 Several lines of evidence indicate that cyclin B1 is also important in the context of cardiovascular disease: its expression has been reported in human restenotic tissue obtained by directional coronary atherectomy, 12 it is induced in balloon-injured rat carotid artery, 13,14 and its inhibition reduces neointimal thickening in this animal model. 15 Herein, we present evidence from 2 independent cohorts of patients undergoing coronary stent deployment (Clinica Mediterranea and Genetic risk factors for In-Stent Hyperplasia study Amsterdam [GEISHA]) 8 cohorts showing that alleles of the SNPs rs350099, rs350104, and rs164390, located in regulatory regions of CCNB1, are associated with higher CCNB1 mRNA expression and increased risk of in-stent restenosis (ISR) after PCI. Furthermore, we identify mole...

Genetic Analysis of Ligation-Induced Neointima Formation in an F2 Intercross of C57BL/6 and FVB/N Inbred Mouse Strains

“…The recruitment of SMCs to neointimal lesions after PCI in humans is partly under genetic control [ 3 , 5 , 6 ]. Similarly, neointimal hyperplasia after different forms of vascular injury or flow-cessation in mice has been found to be highly strain dependent although little is known about the causative gene variants [ 7 , 8 ].…”

An exploratory study of host polymorphisms in genes that clinically characterize breast cancer tumors and pretreatment cognitive performance in breast cancer survivors

“…The opposite contribution was observed for rs350104CT+CC genotypes. The genotypes associated with poorer cognitive performance in the cohorts of women with BC, rs164390–GT+TT, rs350099–CT+CC, and rs350104–TT, are all hypothesized to lead to lower levels of CCNB1 expression via reduced recruitment of transcription factors to the promotor region of the gene 62. This result is contradictory to anticipated findings, as higher cyclin B levels in breast tissue are associated with more severe cancer phenotypes 63,64.…”

Kielin/chordin‐like protein deficiency aggravates pressure overload‐induced cardiac dysfunction and remodeling via P53/P21/CCNB1 signaling in mice

“…32,33 Recent research has also revealed that the expression of CCNB1 increased in human thoracic aortic dissection and the genetic variants in CCNB1 correlated with the risk of coronary in-stent restenosis. 34,35 However, the role of CCNB1 in cardiac remodeling is still unknown. In this article, we observed that CCNB1 was the most significantly up-regulated gene in both cell division and cell cycle pathways, which were among the most affected pathway associated with up-regulated genes in KO TAC mice.…”