Dataset Information

Association of Myocardial Infarction with CDKN2B Antisense RNA 1 (CDKN2B-AS1) rs1333049 Polymorphism in Slovenian Subjects with Type 2 Diabetes Mellitus.

ABSTRACT:

Background

We examined the role of rs1333049 polymorphism of the CDKN2B Antisense RNA 1 (CDKN2B-AS1) on the prevalence of myocardial infarction (MI) in Slovenian subjects with type 2 diabetes mellitus (T2DM).

Methods

A total of 1071 subjects with T2DM were enrolled in this retrospective cross-sectional case-control study. Of the subjects, 334 had a history of recent MI, and 737 subjects in the control group had no clinical signs of coronary artery disease (CAD). With logistic regression, we performed a genetic analysis of rs1333049 polymorphism in all subjects.

Results

The C allele of rs1333049 polymorphism was statistically more frequent in MI subjects (p = 0.05). Subjects with CC genotype had a higher prevalence of MI than the control group in the co-dominant (AOR 1.50, CI 1.02-2.21, p = 0.04) and recessive (AOR 1.38, CI 1.09-1.89, p = 0.04) genetic model.

Conclusions

According to our study, the C allele and CC genotype of rs1333049 polymorphism of CDKN2B-AS1 are possible markers of MI in T2DM subjects in the Slovenian population.

SUBMITTER: Tibaut M

PROVIDER: S-EPMC8952457 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association of Myocardial Infarction with CDKN2B Antisense RNA 1 (CDKN2B-AS1) rs1333049 Polymorphism in Slovenian Subjects with Type 2 Diabetes Mellitus.

Tibaut Miha M Naji Franjo F Petrovič Daniel D

Genes 20220316 3

<h4>Background</h4>We examined the role of rs1333049 polymorphism of the CDKN2B Antisense RNA 1 (CDKN2B-AS1) on the prevalence of myocardial infarction (MI) in Slovenian subjects with type 2 diabetes mellitus (T2DM).<h4>Methods</h4>A total of 1071 subjects with T2DM were enrolled in this retrospective cross-sectional case-control study. Of the subjects, 334 had a history of recent MI, and 737 subjects in the control group had no clinical signs of coronary artery disease (CAD). With logistic regr ...[more]

PMID: 35328079

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Project description:The relationship between Cyclin-Dependent Kinase Inhibitors 2B Antisense RNA 1 (CDKN2B-AS1) variants rs1333049 G/C and rs4977574 A/G and the risk of coronary heart disease is unclear. We conducted an update analysis incorporating odds ratios and 95% confidence intervals to assess the correlation. Furthermore, we used in silico analysis to investigate the genes and proteins that interact with CDKN2B. Fifty case-control studies with a sample size of 35,915 cases and 48,873 controls were involved. We revealed that the rs1333049 C allele could increase the risk of coronary heart disease in the overall analysis (allele comparison, OR = 1.13, 95%CI = 1.05-1.21, P = 0.001; homozygous contrast, OR = 1.29, 95%CI = 1.11-1.49, P = 0.001; dominant comparison, OR = 1.14, 95%CI = 1.03-1.27, P = 0.011; recessive comparison, OR = 1.21, 95%CI = 1.10-1.34, P < 0.001). In subgroup analysis, positive correlations were detected in studies involving West and East Asians and in population-based control studies. The rs4977574 G allele was also a risk factor for coronary heart disease (allelic comparison, P = 0.001; heterozygous comparison, P = 0.003; homozygous comparison, P < 0.001; dominant comparison, P = 0.001). These results indicate correlation of CDKN2B-AS1 rs1333049 G/C and rs4977574 A/G variants may be correlated with the risk of coronary heart disease. Abbreviations CDK: Cyclin Dependent Kinase; CCND: G1/S-specific cyclin-D; CDKN: Cyclin Dependent Kinase Inhibitor; GWAS: Genome-wide association study; CDKN2B-AS1: Cyclin-Dependent Kinase Inhibitors 2B Antisense RNA 1; CHD: Coronary heart disease; MAF: minor allele frequencies; HWE: Hardy-Weinberg equilibrium of controls; CI: confidence interval; COL8A2: Collagen type VIII alpha 2 chain; HB: Hospital-based; ORs: odds ratios; ITGA11: Integrin subunit alpha 11; LTBP: Latent transforming factor beta binding protein; PB: Population-based; IBC: Itmat Broad Care; NA: Not applicable; PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism; MI: Myocardial Infarction; SNP: single nucleotide polymorphism; SMAD: Mothers against decapentaplegic homolog; RT-PCR: Real-time polymerase chain reaction; UK: United Kingdom.

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.

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=9.7x10-5 (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 x 10-25). The inflammatory "TNFA signaling via NFKB" gene set was downregulated the most (Padj=1x10-5 (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<9x10-24). The risk variant rs10757278 altered a binding site of the pathogen responsive transcription factor STAT1 (P=5.8x10-6). 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

Association of Myocardial Infarction with CDKN2B Antisense RNA 1 (CDKN2B-AS1) rs1333049 Polymorphism in Slovenian Subjects with Type 2 Diabetes Mellitus.

Background

Methods

Results

Conclusions

Publications

Association of Myocardial Infarction with CDKN2B Antisense RNA 1 (CDKN2B-AS1) rs1333049 Polymorphism in Slovenian Subjects with Type 2 Diabetes Mellitus.

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