Molecular Genetics and Functional Analysis Implicate CDKN2BAS1-CDKN2B Involvement in POAG Pathogenesis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Enrollment of the Study Subjects
2.2. Molecular Genetic Analysis
2.3. Generation of Luciferase Reporter Constructs and Luciferase Reporter Assay
2.4. Cell Lines and Tissues Used for the Study
2.5. Immunostaining
2.6. CDKN2B-AS1 siRNA Treatment
2.7. β-Galactosidase Assay
2.8. Treatment of Cells with TGF-β1 and TGF-β2
2.9. Semi-Quantitative PCR
3. Results
3.1. Genotype-Phenotype Association Studies for SNP rs4977756
3.2. Potential Regulatory Role of SNP rs4977756
3.3. Transcript Expression of CDKN2B-AS1 Locus in POAG Retina, TM and HEK293T Cells
3.4. CDKN2B-AS1 Regulates the Expression of CDKN2B and CDKN2A Transcripts
3.5. Role of CDKN2B-AS1 in Causing Cellular Senescence and ECM Homeostasis
3.6. TGF-β Signaling in Senescent-Inflammatory Phenotype
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Locus | Genotype | Case (Frequency) | Control (Frequency) | Total (Frequency) | Age and Sex Adjusted Odds Ratio (95% CI) | |
---|---|---|---|---|---|
rs4977756 | GG | 181 (11.6%) | 199 (12.4%) | 380 (12.0%) | 1 |
AG | 691 (44.1%) | 753 (47.1%) | 1444 (45.6%) | 1.02 (0.80, 1.30) | |
AA | 695 (44.4%) | 648 (40.5%) | 1343 (42.4%) | 1.21 (0.94, 1.55) | |
Total | 1567 (49.5%) | 1600 (50.5%) | 3167 |
Locus | # of Risk Alleles | Case (Frequency) | Control (Frequency) | Total (Frequency) | Age and Sex Adjusted Odds Ratio (95% CI) | |
---|---|---|---|---|---|
rs4977756 | 0-1 Risk Alleles (GG or AG) | 872 (55.7%) | 952 (59.5%) | 1824 (57.6%) | 1 |
2 Risk Alleles (AA) | 695 (44.3%) | 648 (40.5%) | 1343 (42.4%) | 1.19 (1.02, 1.39) | |
Total | 1567 (49.5%) | 1600 (50.5%) | 3167 |
rs4977756 | |||||
---|---|---|---|---|---|
POAG Risk Factor | ANOVA p-Value | GG Mean (Std Dev) | AG Mean (Std Dev) | AA Mean (Std Dev) | All Genotypes |
Mean CCT | 0.03 * | 535.80 (39.50) | 535.39 (41.52) | 530.28 (38.32) | 533.22 (39.98) |
Mean IOP | 0.65 | 15.83 (4.57) | 16.03 (3.82) | 16.06 (4.07) | 16.02 (4.02) |
Mean VCDR | 0.1 | 0.54 (0.25) | 0.54 (0.25) | 0.56 (0.25) | 0.55 (0.25) |
Mean RNFL | 0.69 | 77.47 (13.37) | 76.42 (15.19) | 76.21 (15.33) | 76.45 (15.04) |
rs4977756 (0-1 vs. 2 Risk Alleles) | ||||
---|---|---|---|---|
POAG Risk Factor | ANOVA p-Value | 0-1 Risk Alleles Mean (std dev) | 2 Risk Alleles Mean (std dev) | All Genotypes Mean (std dev) |
Mean CCT | 0.008 * | 535.48 (41) | 530.28 (38) | 533.22 (39) |
Mean IOP | 0.65 | 15.99 (3.99) | 16.06 (4.07) | 16.02 (4.02) |
Mean VCDR | 0.033 * | 0.54 (0.25) | 0.56 (0.25) | 0.55 (0.25) |
Mean RNFL | 0.64 | 76.64 (14.8) | 76.21 (15.3) | 76.45 (15.) |
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Rathi, S.; Danford, I.; Gudiseva, H.V.; Verkuil, L.; Pistilli, M.; Vishwakarma, S.; Kaur, I.; Dave, T.V.; O’Brien, J.M.; Chavali, V.R.M. Molecular Genetics and Functional Analysis Implicate CDKN2BAS1-CDKN2B Involvement in POAG Pathogenesis. Cells 2020, 9, 1934. https://doi.org/10.3390/cells9091934
Rathi S, Danford I, Gudiseva HV, Verkuil L, Pistilli M, Vishwakarma S, Kaur I, Dave TV, O’Brien JM, Chavali VRM. Molecular Genetics and Functional Analysis Implicate CDKN2BAS1-CDKN2B Involvement in POAG Pathogenesis. Cells. 2020; 9(9):1934. https://doi.org/10.3390/cells9091934
Chicago/Turabian StyleRathi, Sonika, Ian Danford, Harini V. Gudiseva, Lana Verkuil, Maxwell Pistilli, Sushma Vishwakarma, Inderjeet Kaur, Tarjani Vivek Dave, Joan M. O’Brien, and Venkata R. M. Chavali. 2020. "Molecular Genetics and Functional Analysis Implicate CDKN2BAS1-CDKN2B Involvement in POAG Pathogenesis" Cells 9, no. 9: 1934. https://doi.org/10.3390/cells9091934