Analysis of clinical characteristics and genetic susceptibility of steroid-induced ocular hypertension in patients with uveitis_Chinese Journal of Ocular Fundus Diseases

Authors：

Tao Qingqin ¹ , Zhang Xinyi ¹ , Yang Fuhua ¹ , Liu Zheng ² , Li Xiaorong ¹ ,  Zhang Xiaomin ¹

1. Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;
2. Shanxi Eye Hospital, Taiyuan 030002, China;

Corresponding?author：

Zhang Xiaomin, Email: xzhang08@tmu.edu.cn

Keywords：

Uveitis; Glucocorticoids; Ocular hypertension; Genetic predisposition to disease; Polymorphism, single nucleotide

DOI：

10.3760/cma.j.cn511434-20220119-00040

Video：

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Objective To observe the clinical characteristics of steroid-induced ocular hypertension (SIOH) in patients with uveitis, and explore the relationship between its clinical phenotype and gene polymorphism. Methods A retrospective case-control study. From July 2019 to December 2020, 576 patients with uveitis who were treated with glucocorticoid eye drops in Tianjin Medical University Eye Hospital were included in the study. Among them, there were 175 confirmed glucocorticoid responders (SRs) and 401 glucocorticoid non-responders (NRs). Seventy cases of SRs (age ≥18 years) using 1% prednisone acetate eye drops were selected as the experiment group and 64 cases of NRs were selected as the control group. The polymorphism of rs2523864 and rs3873352 of human leukocyte antigen complex group (HCG) 22 gene were detected by Sanger sequencing. To observe the clinical characteristics of SIOH after the use of glucocorticoid eye drops, and the correlation between rs2523864 and rs3873352 and the occurrence of SIOH. Differences among groups were compared with the Chi-square test or Fisher's exact test. The correlation between the occurrence of SIOH and the range of intraocular pressure increases after glucocorticoid use and the rs2523864 and rs3873352 loci were compared using the odds ratio (OR) and its 95% confidence interval (CI). Results SIOH occurred in 175 (30.4%, 175/576) of 576 patients. Among them, there were 96 males (54.9%, 96/175) and 79 females (45.1%, 79/175); the average age was 33.64±17.40 years. Steroid high responders (HRs) and steroid moderate responders (MRs) were 58 (33.1%, 58/175) and 117 (66.9%, 117/175) cases. The medication time for the increase in intraocular pressure in MRs that was 33 (19, 56) days, and in HRs that was 28 (14, 36) days, the difference of which was significant (Z=－1.999, P=0.046). No differences were found in daily doses of ocular hypertension induced by 1% prednisone acetate eye drops between MRs which was 4.24 (3.46, 4.66) drops/day and HRs that was 4.32 (3.84, 5.36) drops/day (Z=－1.676, P=0.094). The genotype and allele frequency distribution of the rs3873352 locus in the case group and HRs group were significantly different from those in the control group (P＜0.05). The intraocular pressure with rs3873352 GG genotype after the medication was higher than that with GC and CC genotype (Z=2.855, 2.628; P=0.013, 0.026), whereas there was no significant difference between different genotypes of rs2523864 (Z=3.580, P＞0.05). Genetic model analysis revealed the risk of SIOH in rs3873352 G allele carriers (GG+GC) was 2.048 times that of non-G allele carriers (OR=2.048, 95%CI: 1.027-4.081, P=0.041). The genotype and allele frequency of rs2523864 locus showed no significant difference between different group (P＞0.05). Conclusions After the use of glucocorticoid eye drops, HRs have an earlier increase in intraocular pressure than MRs. HCG22-rs3873352 gene polymorphism is related to the occurrence of SIOH, GG genotype increases the risk of SIOH, and G allele is a risk gene for SIOH.

Citation： Tao Qingqin, Zhang Xinyi, Yang Fuhua, Liu Zheng, Li Xiaorong, Zhang Xiaomin. Analysis of clinical characteristics and genetic susceptibility of steroid-induced ocular hypertension in patients with uveitis. Chinese Journal of Ocular Fundus Diseases, 2022, 38(5): 353-358. doi: 10.3760/cma.j.cn511434-20220119-00040 Copy

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25.	Wijffels G, Eisemann C, Riding G, et al. A novel family of chitin-binding proteins from insect type 2 peritrophic matrix. cDNA sequences, chitin binding activity, and cellular localization[J]. J Biol Chem, 2001, 276(18): 15527-15536. DOI: 10.1074/jbc.M009393200.

1. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop[J]. Am J Ophthalmol, 2005, 140(3): 509-516. DOI: 10.1016/j.ajo.2005.03.057.
2. Carnahan MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic corticosteroids[J]. Curr Opin Ophthalmol, 2000, 11(6): 478-483. DOI: 10.1097/00055735-200012000-00016.
3. Jones R 3rd, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature[J]. Curr Opin Ophthalmol, 2006, 17(2): 163-167. DOI: 10.1097/01.icu.0000193079.55240.18.
4. Chan W, Wiggs JL, Sobrin L. The genetic influence on corticosteroid-induced ocular hypertension: a field positioned for discovery[J]. Am J Ophthalmol, 2019, 202: 1-5. DOI: 10.1016/j.ajo.2019.02.001.
5. Becker B, Shin D, Palmberg P, et al. HLA antigens and corticosteroid response[J]. Science, 1976, 194(4272): 1427-1428. DOI: 10.1126/science.1006308.
6. Becker B, Palmberg F, Shin DH. Glucocorticoid responsiveness associated with HLA-B12[J]. Invest Ophthalmol Vis Sci, 1977, 16(1): 61-63.
7. Jeong S, Patel N, Edlund C, et al. Identification of a novel mucin gene HCG22 associated with steroid-induced ocular hypertension[J]. Invest Ophthalmol Vis Sci, 2015, 56(4): 2737-2748. DOI: 10.1167/iovs.14-14803.
8. Szabó V, Borgulya G, Filkorn T, et al. The variant N363S of glucocorticoid receptor in steroid-induced ocular hypertension in Hungarian patients treated with photorefractive keratectomy[J]. Mol Vis, 2007, 13: 659-666.
9. Armaly MF, Becker B. Intraocular pressure response to topical corticosteroids[J]. Fed Proc, 1965, 24(6): 1274-1278.
10. Sulaiman RS, Kadmiel M, Cidlowski JA. Glucocorticoid receptor signaling in the eye[J]. Steroids, 2018, 133: 60-66. DOI: 10.1016/j.steroids.2017.11.002.
11. 裴明杭, 趙潺, 高斐, 等. 兒童及成人葡萄膜炎患者糖皮質激素滴眼液所致高眼壓特點的比較分析[J]. 中華眼科雜志, 2018, 54(11): 839-842. DOI: 10.3760/cma.j.issn.0412-4081.2018.11.008.Pei MH, Zhao C, Gao F, et al. Clinical features of glucocorticoid eye drops induced ocular hypertension in pediatric and adult uveitic eyes[J]. Chin J Ophthalmol, 2018, 54(11): 839-842. DOI: 10.3760/cma.j.issn.0412-4081.2018.11.008.
12. Rhee DJ, Peck RE, Belmont J, et al. Intraocular pressure alterations following intravitreal triamcinolone acetonide[J]. Br J Ophthalmol, 2006, 90(8): 999-1003. DOI: 10.1136/bjo.2006.090340.
13. Armaly MF. The heritable nature of dexamethasone-induced ocular hypertension[J]. Arch Ophthalmol, 1966, 75(1): 32-35. DOI: 10.1001/archopht.1966.00970050034007.
14. Fini ME, Schwartz SG, Gao X, et al. Steroid-induced ocular hypertension/glaucoma: focus on pharmacogenomics and implications for precision medicine[J]. Prog Retin Eye Res, 2017, 56: 58-83. DOI: 10.1016/j.preteyeres.2016.09.003.
15. Harper AR, Topol EJ. Pharmacogenomics in clinical practice and drug development[J]. Nat Biotechnol, 2012, 30(11): 1117-1124. DOI: 10.1038/nbt.2424.
16. Manolio T. Genomewide association studies and assessment of the risk of disease[J]. N Engl J Med, 2010, 363(2): 166-176. DOI: 10.1056/NEJMra0905980.
17. Fingert JH, Alward WL, Wang K, et al. Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders[J]. Mol Vis, 2010, 16: 596-601.
18. Gerzenstein SM, Pletcher MT, Cervino AC, et al. Glucocorticoid receptor polymorphisms and intraocular pressure response to intravitreal triamcinolone acetonide[J]. Ophthalmic Genet, 2008, 29(4): 166-170. DOI: 10.1080/13816810802320217.
19. Hogewind BF, Micheal S, Bakker B, et al. Analysis of single nucleotide polymorphisms in the SFRS3 and FKBP4 genes in corticosteroid-induced ocular hypertension[J]. Ophthalmic Genet, 2012, 33(4): 221-224. DOI: 10.3109/13816810.2012.716488.
20. Hogewind BF, Micheal S, Schoenmaker-Koller FE, et al. Analyses of sequence variants in the MYOC gene and of single nucleotide polymorphisms in the NR3C1 and FKBP5 genes in corticosteroid-induced ocular hypertension[J]. Ophthalmic Genet, 2015, 36(4): 299-302. DOI: 10.3109/13816810.2013.879598.
21. Duan ZX, Gu W, Du DY, et al. Distributions of glucocorticoid receptor gene polymorphisms in a Chinese Han population and associations with outcome after major trauma[J]. Injury, 2009, 40(5): 479-483. DOI: 10.1016/j.injury.2008.09.025.
22. Wang XQ, Duan ZX, He XG, et al. Clinical relevance of the glucocorticoid receptor gene polymorphisms in glucocorticoid-induced ocular hypertension and primary open angle glaucoma[J]. Int J Ophthalmol, 2015, 8(1): 169-173. DOI: 10.3980/j.issn.2222-3959.2015.01.30.
23. Wang N, Chintala SK, Fini ME, et al. Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype[J]. Nat Med, 2001, 7(3): 304-309. DOI: 10.1038/85446.
24. Wordinger RJ, Sharma T, Clark AF. The role of TGF-β2 and bone morphogenetic proteins in the trabecular meshwork and glaucoma[J]. J Ocul Pharmacol Ther, 2014, 30(2-3): 154-162. DOI: 10.1089/jop.2013.0220.
25. Wijffels G, Eisemann C, Riding G, et al. A novel family of chitin-binding proteins from insect type 2 peritrophic matrix. cDNA sequences, chitin binding activity, and cellular localization[J]. J Biol Chem, 2001, 276(18): 15527-15536. DOI: 10.1074/jbc.M009393200.

Chinese Journal of Ocular Fundus Diseases

Analysis of clinical characteristics and genetic susceptibility of steroid-induced ocular hypertension in patients with uveitis

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