Dataset Information

Association of CDKN2B-AS1 rs1333049 with Brain Diseases: A Case-control Study and a Meta-analysis.

ABSTRACT: Objective:CDKN2B-AS1 polymorphisms were shown to associate with the risk of stroke in European. The goal of this study was to evaluate the contribution of CDKN2B-AS1 rs1333049 to the risk of hemorrhagic stroke (HS) and brain tumor (BT) in Han Chinese. Methods:A total of 142 HSs, 115 BTs, and 494 controls were included in the current association study. The genotyping test was performed using the melting temperature shift method. Results:We failed to validate the association of CDKN2B-AS1 rs1333049 with the risk of brain disease. Significantly higher levels of low-density lipoprotein cholesterol (LDL-C) (p=0.027), high-density lipoprotein cholesterol (HDL-C) (p?0.001) and total cholesterol (TC) (p?0.001) were found in HSs in the genotype GG/GC carriers, but not the genotype CC carriers (p?0.05). The meta-analysis of 10 studies among 133,993 individuals concluded that rs1333049 of CDKN2B-AS1 gene was likely to increase a 16% incidence rate of cerebrovascular disease (CD) among various populations (odds ratio 1.16, 95% confidence interval 1.08-1.25; p?0.0001, random-effect method). Conclusion:Our case-control study identified rs1333049 genotypes showed different association with the concentration of the LDL-C, HDL-C and TC in the HS patients. Meta-analysis supported the association between rs1333049 and CD risk in various populations, although we were unable to observe association between rs1333049 and the risk of HSs in Han Chinese.

SUBMITTER: Zhao J

PROVIDER: S-EPMC5290720 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

Association of <i>CDKN2B-AS1</i> rs1333049 with Brain Diseases: A Case-control Study and a Meta-analysis.

Zhao Jikuang J Wu Xizheng X Nie Sheng S Gao Xiang X Sun Jie J Li Keqin K Zhang Tiefeng T Huang Yi Y

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 20170201 1

<h4>Objective</h4><i>CDKN2B-AS1</i> polymorphisms were shown to associate with the risk of stroke in European. The goal of this study was to evaluate the contribution of <i>CDKN2B-AS1</i> rs1333049 to the risk of hemorrhagic stroke (HS) and brain tumor (BT) in Han Chinese.<h4>Methods</h4>A total of 142 HSs, 115 BTs, and 494 controls were included in the current association study. The genotyping test was performed using the melting temperature shift method.<h4>Results</h4>We failed to validate th ...[more]

PMID: 28138111

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Project description:BackgroundVariants in CDKN2B/CDKN2B-AS1 have been reported to modulate glaucoma risk in several GWAS across different populations. CDKN2B/CDKN2A encodes tumor suppressor proteins p16INK4A/p15INK4B which influences cell proliferation/senescence in RGCs, the degeneration of which is a risk factor for glaucoma. CDKN2B-AS1 codes a long non-coding RNA in antisense direction and is involved in influencing nearby CDKN2A/CDKN2B via regulatory mechanisms.MethodsCurrent study investigated four SNPs (rs2157719, rs3217992, rs4977756, rs1063192) of aforementioned genes in a case-control study in a North Indian cohort. Genotyping was done with Taqman chemistry. In addition, an updated meta-analysis was performed.ResultsTwo SNPs, rs3217992 and rs2157719 were found to be significantly associated with the disease. The frequency of 'T' allele of rs3217992 was significantly lower in cases (POAG/PACG) [p = 0.045; OR = 0.80(CI = 0.65-0.99) and p = 0.024; OR = 0.73(CI = 0.55-0.96)], respectively than in controls. Genetic model analysis revealed that TT + CT genotype confers 0.73-fold protection against POAG [p = 0.047; OR = 0.73(CI = 0.54-0.99)] and trend assumed additive model gives 0.53 times higher protection against PACG progression. However the association of rs3217992 with POAG and PACG did not remain significant after Bonferroni correction. For rs2157719, the 'C' allele was found to be less prevalent among cases (POAG/PACG) with respect to controls. Cochran Armitage trend test assuming additive model revealed 0.77 and 0.64-fold protection against POAG and PACG respectively. Bonferroni correction (pcorr = 0.003) was applied and the association of rs2157719 remained significant in PACG cases but not among POAG cases (p = 0.024). The 'CC' genotype also confers protection against primary glaucoma (POAG/PACG) among males and female subjects. The frequency rs1063192 and rs4977756 did not vary significantly among subjects, however the haplotype 'CATA' was found to be associated with increased glaucoma risk. An updated meta-analysis conducted on pooled studies on POAG cases and controls revealed significant association between rs1063192, rs2157719, rs4977756 and POAG except rs3217992.ConclusionThe study concludes significant association between INK4 variants and primary glaucoma in the targeted North Indian Punjabi cohort. We believe that deep-sequencing of INK4 locus may help in identifying novel variants modifying susceptibility to glaucoma. Functional studies can further delineate the role of CDKN2B and CDKN2B-AS1 in primary glaucoma for therapeutic intervention.

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.

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.

Dataset Information

Association of CDKN2B-AS1 rs1333049 with Brain Diseases: A Case-control Study and a Meta-analysis.

Publications

Association of <i>CDKN2B-AS1</i> rs1333049 with Brain Diseases: A Case-control Study and a Meta-analysis.

Similar Datasets

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