Screening for a Deleterious STING1 Polymorphism and its Association with Age-Related Macular Degeneration: A Case-Control Study
Abstract
Background: Inflammation is involved in development of age-related macular degeneration (AMD), with the cGAS-STING pathway playing a critical role. This pathway activates in response to cytosolic DNA, such as accumulated mitochondrial DNA from aging or oxidative stress. Given STING's encoded by the STING1 gene, we hypothesized that functional STING1 polymorphisms might influence AMD susceptibility.
Methods: To identify the most relevant polymorphism, all polymorphisms of STING1 with MAF ≥1% were extracted from NCBI. The rs7380824 was selected for genotyping as it demonstrated the highest PSI value—a novel metric combining CADD score and MAF—indicating high potential deleteriousness. Then a hospital-based case-control study comprised 237 subjects (122 AMD patients, 115 controls) was carried out to investigate the association between the rs7380824 and the risk of AMD. Genotyping employed PCR-RFLP, and statistical analyses used logistic regression adjusted for age, smoking, and workplace exposure.
Results: The genotypic frequency of the rs7380824 polymorphism was in Hardy-Weinberg equilibrium. No significant association was found between the genotypes of this polymorphism and AMD risk. However, a borderline protective effect was observed for the TT genotype versus CC+CT (OR=0.19, 95% CI: 0.03-1.16, p=0.073) after adjusting for age, workplace and smoking habits of the participants.
Conclusion: As the first investigation of the association between the STING1 polymorphism (rs7380824) and AMD risk, this study did not identify a significant overall association. However, the observed protective effect of the TT genotype, potentially covered by the limited sample size, highlights the necessity for validation in studies with larger samples.
2. Tanaka Y, Chen ZJ. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal. 2012;5(214):ra20-ra. https://doi.org/10.1126/scisignal.2002521
3. Chen Q, Tang L, Zhang Y, Wan C, Yu X, Dong Y, et al. STING up-regulates VEGF expression in oxidative stress-induced senescence of retinal pigment epithelium via NF-κB/HIF-1α pathway. Life Sci. 2022;293:120089. https://doi.org/10.1016/j.lfs.2021.120089
4. Mao K, Huang Y, Liu Z, Sui W, Liu C, Li Y, et al. Oxidative stress mediates retinal damage after corneal alkali burn through the activation of the cGAS/STING pathway. Exp Eye Res. 2025;251:110228. https://doi.org/10.1016/j.exer.2024.110228
5. Zou M, Gong L, Ke Q, Qi R, Zhu X, Liu W, et al. Heterochromatin inhibits cGAS and STING during oxidative stress-induced retinal pigment epithelium and retina degeneration. Free Radic Biol Med. 2022;178:147-60. https://doi.org/10.1016/j.freeradbiomed.2021.11.040
6. Zou M, Ke Q, Nie Q, Qi R, Zhu X, Liu W, et al. Inhibition of cGAS-STING by JQ1 alleviates oxidative stress-induced retina inflammation and degeneration. Cell Death Differ. 2022;29(9):1816-33. https://doi.org/10.1038/s41418-022-00967-4
7. Dib B, Lin H, Maidana DE, Tian B, Miller JB, Bouzika P, et al. Mitochondrial DNA has a pro-inflammatory role in AMD. Biochim Biophys Acta, Mol Cell Res. 2015;1853(11):2897-906. https://doi.org/10.1016/j.bbamcr.2024.119790
8. Wu Y, Wei Q, Yu J. The cGAS/STING pathway: a sensor of senescence-associated DNA damage and trigger of inflammation in early age-related macular degeneration. Clin Interv Aging. 2019:1277-83. https://doi.org/10.2147/cia.s200637
9. Zhu X, Liu W, Tang X, Chen Y, Ge X, Ke Q, et al. The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage. J Neuroinflamm. 2023;20(1):119. https://doi.org/10.1186/s12974-023-02804-y
10. DeAngelis MM, Owen LA, Morrison MA, Morgan DJ, Li M, Shakoor A, et al. Genetics of age-related macular degeneration (AMD). Hum Mol Genet. 2017;26(R1):R45-r50. https://doi.org/10.1093/hmg/ddx228.
11. Edwards AO, Ritter R, 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421-4. https://doi.org/10.1126/science.1110189.
12. Zareparsi S, Buraczynska M, Branham KE, Shah S, Eng D, Li M, et al. Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet. 2005;14(11):1449-55. https://doi.org/10.1093/hmg/ddi154.
13. Lin J-M, Wan L, Tsai Y-Y, Lin H-J, Tsai Y, Lee C-C, et al. Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration. American J Ophthalmol. 2008;145(6):1045-51. e2. https://doi.org/10.1016/j.ajo.2008.01.027
14. Kircher M, Witten DM, Jain P, O'roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310-5. https://doi.org/10.1038/ng.2892
15. Kalteh S, Saadat M. Lack of association between three common genetic variations of XPC and susceptibility to age-related macular degeneration, a preliminary study. Egyptian Journal of Medical Human Genetics. 2020;21(1):18.
16. Li T, Chen ZJ. The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med. 2018;215(5):1287-99. https://doi.org/10.1084/jem.20180139
17. Hu B, Ma J-X, Duerfeldt AS. The cGAS–STING pathway in diabetic retinopathy and age-related macular degeneration. Future Med Chem. 2023;15(8):717-29. https://doi.org/10.4155/fmc-2022-0301
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| Issue | Vol 3 No 4 (2025) | |
| Section | Original Articles | |
| Keywords | ||
| Age-related macular degeneration AMD Polymorphism rs7380824 STING1 | ||
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