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Effects of CDKN2B-AS1 polymorphisms on the susceptibility to coronary heart disease.

ABSTRACT: BACKGROUND:Coronary heart disease (CHD) is one of the most severe cardiovascular diseases. Cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) is a significant susceptibility locus for cardiovascular disease by regulating inflammation response and cell cycle. The aim of this study was to assess whether CDKN2B-AS1 polymorphisms are associated with CHD risk in the Chinese Han population. METHODS:A total of 501 CHD patients and 496 healthy controls were recruited from Central South University Xiangya School of Medicine Affiliated Haikou Hospital, five CDKN2B-AS1 polymorphisms (rs10115049, rs75227345, rs2383205, rs10738606, and rs1333049) were analyzed by the Agena MassARRAY platform. The association of CDKN2B-AS1 polymorphisms and CHD risk was determined by odd ratios (OR) and 95% confidence intervals (CI) using logistic regression. RESULTS:CDKN2B-AS1 rs10738606 was significantly associated with CHD under codominant (p = .03), dominant (p = .019), recessive (p = .010), additive (p = .003), and allele (p = .003) models. Gender-based subgroup tests showed that four polymorphisms (rs75227345, rs2383205, rs10738606 and rs1333049) were associated with CHD in males (p < .05). And age-based subgroup tests indicated that rs2383205 and rs10738606 were associated with CHD among individuals, respectively (p < .05). For CHD patients, rs1333049 decreased the risk of diabetes under heterozygote (p = .014) and dominant (p = .024) models. CONCLUSIONS:In conclusion, CDKN2B-AS1 polymorphisms were associated with CHD risk in the combined or subgroup tests, suggesting an important role of CDKN2B-AS1 in CHD susceptibility.

SUBMITTER: Huang K

PROVIDER: S-EPMC6825846 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Effects of CDKN2B-AS1 polymorphisms on the susceptibility to coronary heart disease.

Huang Kang K Zhong Jianghua J Li Qiang Q Zhang Wei W Chen Zibin Z Zhou Yilei Y Wu Miao M Zhong Zanrui Z Lu Shijuan S Zhang Shufang S

Molecular genetics & genomic medicine 20190908 11

<h4>Background</h4>Coronary heart disease (CHD) is one of the most severe cardiovascular diseases. Cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) is a significant susceptibility locus for cardiovascular disease by regulating inflammation response and cell cycle. The aim of this study was to assess whether CDKN2B-AS1 polymorphisms are associated with CHD risk in the Chinese Han population.<h4>Methods</h4>A total of 501 CHD patients and 496 healthy controls were recruited from C ...[more]

PMID: 31496134

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Project description:BackgroundNumerous genetic variations in inflammasome components are linked to prevalent disorders in the general population, including periodontitis and cardiovascular illness. Polymorphisms in the genes play a critical in the initiation and development of inflammatory diseases. The limited study on AIM2 gene variation associated with inflammatory disease and no study of PYCARD gene variation associated with inflammatory disease.ObjectiveThis case-control study was to examine the association between the single nucleotide polymorphism of AIM2 and Pycard genes with susceptibility to periodontitis with and without coronary heart disease, to determine interleuken-18 and gasdermin D levels in the saliva of periodontitis with and without coronary heart disease patients, as well as their correlation with salivary interleuken-18 and gasdermin D levels and clinical periodontal parameters.MethodsThe present study recruited 120 participants: 30 were healthy subjects (control, C), 30 had generalized periodontitis (P), 30 had atherosclerosis coronary heart disease with clinically healthy periodontium (AS-C), and 30 had atherosclerosis coronary heart disease with generalized periodontitis (AS-P). All individuals' demographic data recorded, saliva and blood samples collected, then periodontal characteristics were detailed. These parameters include plaque index, bleeding on probing, probing pocket depth, and clinical attachment loss. AIM2 and Pycard gene polymorphisms were analyzed by polymerase chain reaction assay, electrophoresis and sequencing. An enzyme-linked immunosorbent assay (ELISA) was conducted to determine the level of interleuken-18 and gasdermin D in their saliva.ResultsThe study result of high frequency (T) in single-nucleotide polymorphisms. The high genotypes distribution of GT and TT genotypes in the AIM2 gene and the CT and TT genotypes in the Pycard gene were detected in the periodontitis, atherosclerosis coronary heart disease with healthy periodontium and atherosclerosis coronary heart disease with generalized periodontitis groups as compared to control group. Elevation of salivary interleuken-18 and gasdermin D levels in three patients' groups compared to healthy controls. Both these single-nucleotide polymorphisms also significantly correlated with higher salivary interleuken-18 and gasdermin D levels and worse clinical indices of periodontitis.ConclusionSingle-nucleotide polymorphisms in the AIM2 and Pycard genes are associated with an increased risk of developing periodontitis with and/or without coronary heart disease. Elevation of salivary interleuken-18 and gasdermin D levels associated and impacted on periodontitis with and/or without coronary heart disease. These single-nucleotide polymorphisms may provide evidence for a genetic role in the pathogenesis of periodontitis with and without atherosclerosis coronary heart disease.

Project description:The long noncoding RNA CDKN2B-AS1 harbors a major coronary artery disease risk haplotype, which is also associated with progressive forms of the oral inflammatory disease periodontitis as well as myocardial infarction (MI). Despite extensive research, there is currently no broad consensus on the function of CDKN2B-AS1 that would explain a common molecular role of this lncRNA in these diseases. Our aim was to investigate the role of CDKN2B-AS1 in gingival cells to better understand the molecular mechanisms underlying the increased risk of progressive periodontitis. We downregulated CDKN2B-AS1 transcript levels in primary gingival fibroblasts with LNA GapmeRs. Following RNA-sequencing, we performed differential expression, gene set enrichment analyses and Western Blotting. Putative causal alleles were searched by analyzing associated DNA sequence variants for changes of predicted transcription factor binding sites. We functionally characterized putative functional alleles using luciferase-reporter and antibody electrophoretic mobility shift assays in gingival fibroblasts and HeLa cells. Of all gene sets analysed, collagen biosynthesis was most significantly upregulated (Padj=9.7 × 10- 5 (AUC > 0.65) with the CAD and MI risk gene COL4A1 showing strongest upregulation of the enriched gene sets (Fold change = 12.13, Padj = 4.9 × 10- 25). The inflammatory "TNFA signaling via NFKB" gene set was downregulated the most (Padj=1 × 10- 5 (AUC = 0.60). On the single gene level, CAPNS2, involved in extracellular matrix organization, was the top upregulated protein coding gene (Fold change = 48.5, P < 9 × 10- 24). The risk variant rs10757278 altered a binding site of the pathogen responsive transcription factor STAT1 (P = 5.8 × 10- 6). rs10757278-G allele reduced STAT1 binding 14.4% and rs10757278-A decreased luciferase activity in gingival fibroblasts 41.2% (P = 0.0056), corresponding with GTEx data. CDKN2B-AS1 represses collagen gene expression in gingival fibroblasts. Dysregulated collagen biosynthesis through allele-specific CDKN2B-AS1 expression in response to inflammatory factors may affect collagen synthesis, and in consequence tissue barrier and atherosclerotic plaque stability.

Dataset Information

Effects of CDKN2B-AS1 polymorphisms on the susceptibility to coronary heart disease.

Publications

Effects of CDKN2B-AS1 polymorphisms on the susceptibility to coronary heart disease.

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