Associations of Tumor Necrosis Factor-Alpha Gene Polymorphisms (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-Alpha Serum Concentration with Age-Related Macular Degeneration
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Subjects
- Early AMD consists of a combination of multiple small drusen (protein and lipid deposit) formation between the RPE and BrM [21] and several intermediate (63–124 μm in diameter) drusen or retinal pigment epithelial abnormalities; may not cause any symptoms.
- The intermediate form is described as a presence of at least one large (≥125 μm in diameter) drusen, numerous medium-sized drusen, or GA without extension to the center of the macula with mild symptoms, as mild blurriness in their central vision or trouble seeing in low lighting or may not cause any symptoms.
- The advanced AMD is divided into:
- Dry/atrophic AMD with the GA of the RPE;
- Neovascular or exudative AMD, which is diagnosed when choroidal neovascularization with detachments in the RPE hemorrhages and/or scars appear and cause progressive blurring or other central vision impairments [22].
- Unrelated eye disorders, e.g., high refractive error, cloudy cornea, lens opacity (nuclear, cortical, or posterior subcapsular cataract) except minor opacities, keratitis, acute or chronic uveitis, glaucoma, or diseases of the optic nerve.
- Any other inflammatory diseases.
- Systemic illnesses, e.g., diabetes mellitus, malignant tumors, systemic connective tissue disorders, chronic infectious and noninfectious diseases, hypertension, coronary artery disease, stroke or conditions following organ or tissue transplantation.
- Ungraded color fundus photographs resulting from obscuring the ocular optic system or because of fundus photograph quality.
- Use of antiepileptic or sedative drugs.
2.2. Deoxyribonucleic Acid Extraction
2.3. Measurement of DNA Concentration by Spectrophotometer
2.4. Detection of Single-Nucleotide Polymorphisms by a RT-PCR
2.5. Determination of Serum TNF-α Protein by ELISA
2.6. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Sharma, K.; Sharma, N.K.; Anand, A. Why AMD is a disease of ageing and not of development: Mechanisms and insights. Front. Aging Neurosci. 2014, 6, 151. [Google Scholar] [CrossRef] [Green Version]
- Yan, Q.; Ding, Y.; Weeks, D.E.; Chen, W. AMD genetics: Methods and analyses for association, progression, and prediction. Adv. Exp. Med. Biol. 2021, 1256, 191–200. [Google Scholar]
- García-Layana, A.; Cabrera-López, F.; García-Arumí, J.; Arias-Barquet, L.; Ruiz-Moreno, J.M. Early and intermediate age-related macular degeneration: Update and clinical review. Clin. Interv. Aging 2017, 12, 1579–1587. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sergejeva, O.; Botov, R.; Liutkevičienė, R.; Kriaučiūnienė, L. Genetic factors associated with the development of age-related macular degeneration. Medicina 2016, 52, 79–88. [Google Scholar] [CrossRef]
- Stahl, A. The diagnosis and treatment of age-related macular degeneration. Dtsch. Arztebl. Int. 2020, 117, 513–520. [Google Scholar] [CrossRef]
- Wong, W.L.; Su, X.; Li, X.; Cheung, C.M.; Klein, R.; Cheng, C.Y.; Wong, T.Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e106–e116. [Google Scholar] [CrossRef] [Green Version]
- Cascella, R.; Ragazzo, M.; Strafella, C.; Missiroli, F.; Borgiani, P.; Angelucci, F.; Marsella, L.T.; Cusumano, A.; Novelli, G.; Ricci, F.; et al. Age-related mac-ular degeneration: Insights into inflammatory genes. J. Ophthalmol. 2014, 2014, 582842. [Google Scholar]
- Mathenge, W. Age-related macular degeneration. Community Eye Health 2014, 27, 49–50. [Google Scholar]
- Al-Zamil, W.M.; Yassin, S.A. Recent developments in age-related macular degeneration: A review. Clin. Interv. Aging 2017, 12, 1313–1330. [Google Scholar] [CrossRef] [Green Version]
- Ding, X.; Patel, M.; Chan, C.C. Molecular pathology of age-related macular degeneration. Prog. Retin. Eye Res. 2009, 28, 1–18. [Google Scholar] [CrossRef] [Green Version]
- Ratnapriya, R.; Chew, E.Y. Age-related macular degeneration—Clinical review and genetics up-date. Clin. Genet. 2013, 84, 160–166. [Google Scholar] [CrossRef] [PubMed]
- Schwartz, S.G.; Hampton, B.M.; Kovach, J.L.; Brantley, M.A., Jr. Genetics and age-related macular degeneration: A practical review for the clinician. Clin. Ophthalmol. 2016, 10, 1229–1235. [Google Scholar] [CrossRef] [Green Version]
- Hammond, C.J.; Webster, A.R.; Snieder, H.; Bird, A.C.; Gilbert, C.E.; Spector, T.D. Genetic influence on early age-related maculopathy: A twin study. Ophthalmology 2002, 109, 730–736. [Google Scholar] [CrossRef]
- DeAngelis, M.M.; Owen, L.A.; Morrison, M.A.; Morgan, D.J.; Li, M.; Shakoor, A.; Vitale, A.; Iyengar, S.; Stambolian, D.; Kim, I.K.; et al. Genetics of age-related macular degeneration (AMD). Hum. Mol. Genet 2017, 26, R45–R50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DeAngelis, M.M.; Silveira, A.C.; Carr, E.A.; Kim, I.K. Genetics of age-related macular degeneration: Current concepts, future directions. Semin. Ophthalmol. 2011, 26, 77–93. [Google Scholar] [CrossRef] [PubMed]
- Chernykh, V.; Shevchenko, A.; Konenkov, V.; Prokofiev, V.; Eremina, A.; Trunov, A. TNF-α gene polymorphisms: Association with age-related macular degeneration in Russian population. Int. J. Ophthalmol. 2019, 12, 25–29. [Google Scholar]
- Mirshahi, A.; Hoehn, R.; Lorenz, K.; Kramann, C.; Baatz, H. Anti-tumor necrosis factor alpha for retinal diseases: Current knowledge and future concepts. J. Ophthalmic. Vis. Res. 2012, 7, 39–44. [Google Scholar]
- Parameswaran, N.; Patial, S. Tumor necrosis factor-α signaling in macrophages. Crit. Rev. Eukaryot. Gene Expr. 2010, 20, 87–103. [Google Scholar] [CrossRef]
- El-Tahan, R.R.; Ghoneim, A.M.; El-Mashad, N. TNF-α gene polymorphisms and expression. Springerplus 2016, 5, 1508. [Google Scholar] [CrossRef] [Green Version]
- The Age-Related Eye Disease Study system for classifying age-related macular degeneration from stereoscopic color fundus photographs: The Age-Related Eye Disease Study Report Number 6. Am. J. Ophthalmol. 2001, 132, 668–681. [CrossRef]
- Smith, W.; Assink, J.; Klein, R.; Mitchell, P.; Klaver, C.C.W.; Klein, B.E.K.; Hofman, A.; Jensen, S.; Wang, J.J.; de Jong, P.T. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 2001, 108, 697–704. [Google Scholar] [CrossRef]
- Charles, P. Wilkinson APSDRHSJRPW. In Retina, 4th ed.; Elsevier-Health Sciences Division: Amsterdam, The Netherlands, 2006; Volume 3. [Google Scholar]
- Xu, T.; Kong, Z.; Zhao, H. Relationship between tumor necrosis factor-α rs361525 polymorphism and gastric cancer risk: A meta-analysis. Front. Physiol. 2018, 9, 469. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Y.; Cui, X.; Ning, L.; Wei, D. The effects of tumor necrosis factor-α (TNF-α) rs1800629 and rs361525 polymorphisms on sepsis risk. Oncotarget 2017, 8, 111456–111469. [Google Scholar] [CrossRef] [Green Version]
- Shi, L.X.; Zhang, L.; Zhang, D.L.; Zhou, J.P.; Jiang, X.J.; Jin, Y.L.; Chang, W.W. Association between TNF-α G-308A (rs1800629) polymorphism and susceptibility to chronic periodontitis and type 2 diabetes mellitus: A meta-analysis. J. Periodontal. Res. 2021, 56, 226–235. [Google Scholar] [CrossRef]
- Khan, S.; Mandal, R.K.; Jawed, A.; Dar, S.A.; Wahid, M.; Panda, A.K.; Areeshi, M.Y.; Khan, M.E.A.; Haque, S. TNF-α -308 G > A (rs1800629) polymorphism is associated with celiac disease: A meta-analysis of 11 case-control stu-dies. Sci. Rep. 2016, 6, 32677. [Google Scholar] [CrossRef] [Green Version]
- Han, S.H.; Lee, N.R.; Kim, H.J.; Kang, Y.D.; Kim, J.S.; Park, J.W.; Jin, H.J. Association between the IL-6, IL-10, and TNFα gene polymorphisms and preterm-birth in Korean women. Genes Genomics. 2020, 42, 743–750. [Google Scholar] [CrossRef]
- Gao, S.; Liang, W.; Xu, T.; Xun, C.; Cao, R.; Deng, Q.; Zhang, J.; Sheng, W. Associations of tumor necrosis factor alpha gene polymorphisms and ankylosing spondylitis susceptibility: A meta-analysis based on 35 case-control studies. Immunol. Investig. 2021, 51, 859–882. [Google Scholar] [CrossRef]
- Moorchung, N.N.; Vasudevan, B.; Chatterjee, M.; Grewal, R.S.; Mani, N.S. A comprehensive study of tumor necrosis factor-alpha genetic polymorphisms, its expression in skin and relation to histopatho-logical features in psoriasis. Indian. J. Dermatol. 2015, 60, 345–350. [Google Scholar]
- Behniafard, N.; Gharagozlou, M.; Farhadi, E.; Khaledi, M.; Sotoudeh, S.; Darabi, B.; Fathi, S.M.; Moghaddam, Z.G.; Mahmoudi, M.; Aghamohammadi, A.; et al. TNF-alpha single nucleotide polymorphisms in atopic dermatitis. Eur. Cytokine Netw. 2012, 23, 163–165. [Google Scholar] [CrossRef] [Green Version]
- Albert, R.; Kristóf, E.; Zahuczky, G.; Szatmári-Tóth, M.; Veréb, Z.; Oláh, B.; Moe, M.C.; Facskó, A.; Fésüs, L.; Petrovski, G. Triamcinolone regulated apopto-phagocytic gene expression patterns in the clearance of dying retinal pigment epithelial cells. A key role of Mertk in the enhanced phagocytosis. Biochim. Biophys. Acta. 2015, 1850, 435–446. [Google Scholar] [CrossRef]
- Guo, S.; Yin, H.; Zheng, M.; Tang, Y.; Lu, B.; Chen, X.; Fu, Q.; Qin, Z.; Lyu, D.; Tang, Q.; et al. Cytokine profiling reveals increased serum inflammatory cytokines in idiopathic choroidal neovascularization. BMC Ophthalmol. 2019, 19, 94. [Google Scholar] [CrossRef] [Green Version]
- Nagineni, C.N.; Kommineni, V.K.; William, A.; Detrick, B.; Hooks, J.J. Regulation of VEGF expression in human retinal cells by citokines: Implications for the role of inflammation in age-related macular degeneration. J. Cell Physiol. 2012, 227, 116–126. [Google Scholar] [CrossRef]
- Zahorska-Markiewicz, B.; Janowska, J.; Olszanecka-Glinianowicz, M.; Zurakowski, A. Serum con-centrations of TNF-alpha and soluble TNF-alpha receptors in obesity. Int. J. Obes. 2000, 24, 1392–1395. [Google Scholar] [CrossRef] [Green Version]
- Fan, N.; Luo, Y.; Xu, K.; Zhang, M.; Ke, X.; Huang, X.; Ding, Y.; Wang, D.; Ning, Y.; Deng, X.; et al. Relationship of serum levels of TNF-α, IL-6 and IL-18 and schizophrenia-like symptoms in chronic ketamine abusers. Schizophr. Res. 2015, 169, 10–15. [Google Scholar] [CrossRef] [Green Version]
Control Group n = 355 | Early AMD n = 330 | Exudative AMD n = 393 | p-Value | |
---|---|---|---|---|
Female, n (%) | 222 (62.5) | 227 (68.8) | 254 (64.6) | * 1–0.085 * 2–0.552 |
Male, n (%) | 133 (37.5) | 103 (31.2) | 139 (35.4) | |
Age, median/min./max. | 72/51/94 | 73/42/94 | 77/49/95 | ** 1–0.266 ** 2–<0.001 |
SNP | Genotypes/ Alleles | Group | p-Value | |
---|---|---|---|---|
Control n (%) (n = 355) | Exudative AMD n (%) (n = 393) | |||
TNF-863A/C (rs1800630) | CC | 258 (72.7) | 263 (66.9) | 0.087 |
AC | 87 (24.5) | 108 (27.5) | ||
AA | 10 (2.8) | 22 (5.6) | ||
C | 603 (84.9) | 634 (80.7) | ||
A | 107 (15.1) | 152 (19.3) | 0.029 | |
TNF-308A/G (rs1800629) | GG | 277 (78.0) | 297 (75.6) | 0.730 |
AG | 74 (20.8) | 91 (23.2) | ||
AA | 4 (1.1) | 5 (1.3) | ||
G | 628 (88.5) | 685 (87.2) | ||
A | 82 (11.5) | 101 (12.8) | 0.443 | |
TNF-238A/G (rs361525) | GG | 316 (89.0) | 361 (91.9) | 0.310 |
AG | 38 (10.7) | 30 (7.6) | ||
AA | 1 (0.3) | 2 (0.5) | ||
G | 670 (94.4) | 752 (95.7) | ||
A | 40 (5.6) | 34 (4.3) | 0.244 |
rs1800630 (D′; r2) | rs1800629 (D′; r2) | rs361525 (D′; r2) | |
---|---|---|---|
rs1800630 (D′; r2) | . | 0.832; 0.424 | 0.993; 0.009 |
rs1800629 (D′; r2) | . | . | 0.996; 0.016 |
rs361525 (D′; r2) | . | . | . |
rs1800630 (D′; r2) | rs1800629 (D′; r2) | rs361525 (D′; r2) | |
---|---|---|---|
rs1800630 (D′; r2) | . | 0.414; 0.138 | 0.994; 0.011 |
rs1800629 (D′; r2) | . | . | 0.995; 0.013 |
rs361525 (D′; r2) | . | . | . |
TNF-863A/C (rs1800630) | TNF-308A/G (rs1800629) | TNF-238A/G (rs361525) | Frequency | OR (95% CI) | p-Value | |
---|---|---|---|---|---|---|
Control | Exudative AMD | |||||
C | G | G | 0.691 | 0.657 | 1.00 | – |
C | A | G | 0.104 | 0.112 | 1.13 (0.79–1.62) | 0.5 |
A | A | G | 0.134 | 0.055 | 0.12 (0.05–1.29) | <0.0001 |
A | G | G | 0.016 | 0.131 | 24.45 (9.39–63.63) | <0.0001 |
C | G | A | 0.056 | 0.043 | 0.78 (0.47–1.28) | 0.32 |
C | A | A | 0 | 0.003 | – | – |
SNP | Genotypes/ Alleles | Female | p-Value | Male | p-Value | ||
---|---|---|---|---|---|---|---|
Control n (%) (n = 222) | Exudative AMD n (%) (n = 254) | Control n (%) (n = 133) | Exudative AMD n (%) (n = 139) | ||||
TNF-863A/C (rs1800630) | CC | 163 (73.4) | 163 (64.2) | 0.094 | 95 (71.4) | 100 (71.9) | 0.088 |
AC | 50 (22.5) | 76 (29.9) | 37 (27.8) | 32 (23.0) | |||
AA | 9 (4.1) | 15 (5.9) | 1 (0.8) | 7 (5.0) | |||
C | 376 (84.7) | 402 (79.1) | 227 (85.3) | 232 (83.5) | |||
A | 68 (15.3) | 106 (20.9) | 0.027 | 39 (14.7) | 46 (16.5) | 0.545 | |
TNF-308A/G (rs1800629) | GG | 174 (78.4) | 191 (75.2) | 0.688 | 103 (77.4) | 106 (76.3) | 0.914 |
AG | 46 (20.7) | 61 (24.0) | 28 (21.1) | 30 (21.6) | |||
AA | 2 (0.9) | 2 (0.8) | 2 (1.5) | 3 (2.2) | |||
G | 394 (88.7) | 443 (87.2) | 234 (88.0) | 242 (87.1) | |||
A | 50 (11.3) | 65 (12.8) | 0.469 | 32 (12.0) | 36 (12.9) | 0.746 | |
TNF-238A/G (rs361525) | GG | 199 (89.6) | 233 (91.7) | 0.460 | 117 (88.0) | 128 (92.1) | 0.115 |
AG | 22 (9.9) | 21 (8.3) | 16 (12.0) | 9 (6.5) | |||
AA | 1 (0.5) | 0 (0.0) | 0 (0.0) | 2 (1.4) | |||
G | 420 (94.6) | 487 (95.9) | 250 (94.0) | 265 (95.3) | |||
A | 24 (5.4) | 21 (4.1) | 0.356 | 16 (6.0) | 13 (4.7) | 0.487 |
SNP | Genotypes/ Alleles | Female | p-Value | Male | p-Value | ||
---|---|---|---|---|---|---|---|
Early AMD n (%) (n = 227) | Exudative AMD n (%) (n = 254) | Early AMD n (%) (n = 103) | Exudative AMD n (%) (n = 139) | ||||
TNF-863A/C (rs1800630) | CC | 169 (74.4) | 163 (64.2) | 0.051 | 66 (64.1) | 100 (71.9) | 0.371 |
AC | 49 (21.6) | 76 (29.9) | 32 (31.1) | 32 (23.0) | |||
AA | 9 (4.0) | 15 (5.9) | 5 (4.9) | 7 (5.0) | |||
C | 387 (85.2) | 402 (79.1) | 164 (79.6) | 232 (83.5) | |||
A | 67 (14.8) | 106 (20.9) | 0.014 | 42 (20.4) | 46 (16.5) | 0.279 | |
TNF-308A/G (rs1800629) | GG | 185 (81.5) | 191 (75.2) | 0.056 | 82 (79.6) | 106 (76.3) | 0.824 |
AG | 37 (16.3) | 61 (24.0) | 19 (18.4) | 30 (21.6) | |||
AA | 5 (2.2) | 2 (0.8) | 2 (1.9) | 3 (2.2) | |||
G | 407 (89.6) | 443 (87.2) | 183 (88.8) | 242 (87.1) | |||
A | 47 (10.4) | 65 (12.8) | 0.238 | 23 (11.2) | 36 (12.9) | 0.553 | |
TNF-238A/G (rs361525) | GG | 207 (91.2) | 233 (91.7) | 0.831 | 96 (93.2) | 128 (92.1) | 0.473 |
AG | 20 (8.8) | 21 (8.3) | 7 (6.8) | 9 (6.5) | |||
AA | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (1.4) | |||
G | 434 (95.6) | 487 (95.9) | 199 (96.6) | 265 (95.3) | |||
A | 20 (4.4) | 21 (4.1) | 0.835 | 7 (3.4) | 13 (4.7) | 0.485 |
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Zazeckyte, G.; Gedvilaite, G.; Vilkeviciute, A.; Kriauciuniene, L.; Balciuniene, V.J.; Mockute, R.; Liutkeviciene, R. Associations of Tumor Necrosis Factor-Alpha Gene Polymorphisms (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-Alpha Serum Concentration with Age-Related Macular Degeneration. Life 2022, 12, 928. https://doi.org/10.3390/life12070928
Zazeckyte G, Gedvilaite G, Vilkeviciute A, Kriauciuniene L, Balciuniene VJ, Mockute R, Liutkeviciene R. Associations of Tumor Necrosis Factor-Alpha Gene Polymorphisms (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-Alpha Serum Concentration with Age-Related Macular Degeneration. Life. 2022; 12(7):928. https://doi.org/10.3390/life12070928
Chicago/Turabian StyleZazeckyte, Guoda, Greta Gedvilaite, Alvita Vilkeviciute, Loresa Kriauciuniene, Vilma Jurate Balciuniene, Ruta Mockute, and Rasa Liutkeviciene. 2022. "Associations of Tumor Necrosis Factor-Alpha Gene Polymorphisms (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-Alpha Serum Concentration with Age-Related Macular Degeneration" Life 12, no. 7: 928. https://doi.org/10.3390/life12070928