Genetic polymorphisms and uveitis

IF 3 3区医学 Q1 OPHTHALMOLOGY Acta Ophthalmologica Pub Date : 2025-01-19 DOI:10.1111/aos.16886

Stéphane Abramowicz

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Stochastic factors may also play a role in disease genesis.2\n \n In the context of uveitis, genetic polymorphisms in genes of the class I major histocompatibility complex (MHC), such as HLA-A, or HLA-B, are associated with common non-infectious uveitides (NIU) like HLA-B27-associated acute anterior uveitis (AAU), Behçet's disease, and Birdshot retinochoroiditis (BRC).3\n \n Specifically, HLA-B27 carrier frequency in the Caucasian US population is around 7%, while it is present in approximately 50% of patients who develop AAU, and 90% of patients who develop ankylosing spondylitis (AS). This represents a relative risk (RR) for carriers of HLA-B27 of around 8 for developing AAU,4 and around 50 to 100 for developing AS.5\n \n HLA-B51 carrier frequency in populations along the Silk Road is around 10-30%,6 compared to 50-80% in Behçet's disease patients, conferring a RR of 5-10 to develop the disease.7\n \n The third major HLA polymorphism associated with uveitis is HLA-A29, whose carrier frequency in the Western European population is reported to be 5-10%,8 compared to the 97.5% in BRC patients,3,9 conferring an astronomically high RR of 50-224 for developing BRC in carriers of HLA-A29 versus non-carriers.4,9 BRC is actually the immunological disease with the strongest HLA association ever described.4\n \n Some weaker HLA associations have been reported with other NIU entities, such as HLA-DR4/HLA-DRB1*04 with Vogt-Koyanagi-Harada disease,10,11 HLA-DRB1*04:05, HLA-DQB1*04:01, and the DRB1*04:05-DQB1*04:01 haplotype with sympathetic ophthalmia,12 or HLA-DRB1*15:01 and the IL2-RA gene polymorphism rs2104286 A>G with multiple sclerosis-associated uveitis.13\n \n In addition to HLA typing and polymorphisms, there has been much interest in evaluating single-nucleotide polymorphisms of various mediators of the immune response. For example, polymorphisms in the ERAP1, ERAP2 or IL-23R genes, have been described in association with uveitis.14,15 Many other associations have been described.\n \n That being said, the reason why these genetic associations predispose individuals to immunological disease remains a mystery. Some of the hypotheses put forward over the years include interaction of the HLA molecules with the gut microbiome resulting in increased gut permeability and leakage of bacterial products in the circulation, while others think molecular mimicry acting as a trigger for activation of autoreactive lymphocytes specific for the neuroretina might play a role.16–18\n \n In summary, genetic polymorphisms play a major role in the immunogenetics of some prevalent NIU entities. These may help shape our understanding of pathophysiological mechanisms in the future.\n \n <div>References:<ol>\n \n <li>Hou S, Li N, Liao X, Kijlstra A, Yang P. Uveitis genetics. Exp Eye Res. 2020;190:107853. doi:10.1016/j.exer.2019.107853</li>\n \n <li>Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. Eighth edition. Elsevier; 2016.</li>\n \n <li>Kuiper JJ, Prinz JC, Stratikos E, et al. EULAR study group on “MHC-I-opathy”: identifying disease-overarching mechanisms across disciplines and borders. Ann Rheum Dis. 2023;82(7):887-896. doi:10.1136/ard-2022-222852</li>\n \n <li>Feltkamp TE. Ophthalmological significance of HLA associated uveitis. Eye (Lond). 1990;4 (Pt 6):839-844. doi:10.1038/eye.1990.133</li>\n \n <li>Kopplin LJ, Mount G, Suhler EB. Review for Disease of the Year: Epidemiology of HLA-B27 Associated Ocular Disorders. Ocul Immunol Inflamm. 2016;24(4):470-475. doi:10.1080/09273948.2016.1175642</li>\n \n <li>Horie Y, Meguro A, Ohta T, et al. HLA-B51 Carriers are Susceptible to Ocular Symptoms of Behçet Disease and the Association between the Two Becomes Stronger towards the East along the Silk Road: A Literature Survey. Ocul Immunol Inflamm. 2017;25(1):37-40. doi:10.3109/09273948.2015.1136422</li>\n \n <li>Takeno M. The association of Behçet's syndrome with HLA-B51 as understood in 2021. Curr Opin Rheumatol. 2022;34(1):4-9. doi:10.1097/BOR.0000000000000846</li>\n \n <li>Kuiper JJW, Venema WJ. HLA-A29 and Birdshot Uveitis: Further Down the Rabbit Hole. Front Immunol. 2020;11:599558. doi:10.3389/fimmu.2020.599558</li>\n \n <li>Wee R, Papaliodis G. Genetics of Birdshot Chorioretinopathy. Seminars in Ophthalmology. 2008;23(1):53-57. doi:10.1080/08820530701745231</li>\n \n <li>Davis JL, Mittal KK, Freidlin V, et al. HLA associations and ancestry in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Ophthalmology. 1990;97(9):1137-1142. doi:10.1016/s0161-6420(90)32446-6</li>\n \n <li>Shi T, Lv W, Zhang L, Chen J, Chen H. Association of HLA-DR4/HLA-DRB1*04 with Vogt-Koyanagi-Harada disease: a systematic review and meta-analysis. Sci Rep. 2014;4:6887. doi:10.1038/srep06887</li>\n \n <li>Zhao T, Cao Q, Zhou C, Wang Y, Du L, Yang P. Association Between HLA Polymorphisms and Sympathetic Ophthalmia in Han Chinese. Ocul Immunol Inflamm. Published online May 5, 2023:1-8. doi:10.1080/09273948.2023.2205930</li>\n \n <li>Casselman P, Cassiman C, Casteels I, Schauwvlieghe PP. Insights into multiple sclerosis-associated uveitis: a scoping review. Acta Ophthalmol. 2021;99(6):592-603. doi:10.1111/aos.14697</li>\n \n <li>Gelfman S, Monnet D, Ligocki AJ, et al. ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers. Invest Ophthalmol Vis Sci. 2021;62(14):3. doi:10.1167/iovs.62.14.3</li>\n \n <li>Jung JH, Song GG, Kim JH, Seo YH, Choi SJ. The association between genetic polymorphisms of the interleukin-23 receptor gene and susceptibility to uveitis: a meta-analysis. BMC Ophthalmol. 2017;17(1):81. doi:10.1186/s12886-017-0477-4</li>\n \n <li>Rosenbaum JT, Asquith M. The microbiome and HLA-B27-associated acute anterior uveitis. Nat Rev Rheumatol. 2018;14(12):704-713. doi:10.1038/s41584-018-0097-2</li>\n \n <li>Asquith M, Sternes PR, Costello ME, et al. HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome. Arthritis Rheumatol. 2019;71(10):1642-1650. doi:10.1002/art.40917</li>\n \n <li>Horai R, Caspi RR. Microbiome and Autoimmune Uveitis. 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引用次数: 0

Abstract

Uveitis is a multifactorial disease, originating from the interplay between our genes, the environment and stochastic factors.¹ In contrast, only a handful of exceptional uveitic entities are monogenic.

To understand the immunogenetics of uveitis, one must understand the concept of multifactorial disease. These diseases are characterized by multigenic involvement, with any one variant allele being neither necessary nor sufficient for disease initiation. Rather, it is the combination of multiple variants in multiple genes, which all increase the susceptibility of an individual to develop a particular disease. The second concept is that of the environmental trigger, such as an infection or exposure to a drug, which triggers the disease in genetically susceptible individuals. Stochastic factors may also play a role in disease genesis.²

In the context of uveitis, genetic polymorphisms in genes of the class I major histocompatibility complex (MHC), such as HLA-A, or HLA-B, are associated with common non-infectious uveitides (NIU) like HLA-B27-associated acute anterior uveitis (AAU), Behçet's disease, and Birdshot retinochoroiditis (BRC).³

Specifically, HLA-B27 carrier frequency in the Caucasian US population is around 7%, while it is present in approximately 50% of patients who develop AAU, and 90% of patients who develop ankylosing spondylitis (AS). This represents a relative risk (RR) for carriers of HLA-B27 of around 8 for developing AAU,⁴ and around 50 to 100 for developing AS.⁵

HLA-B51 carrier frequency in populations along the Silk Road is around 10-30%,⁶ compared to 50-80% in Behçet's disease patients, conferring a RR of 5-10 to develop the disease.⁷

The third major HLA polymorphism associated with uveitis is HLA-A29, whose carrier frequency in the Western European population is reported to be 5-10%,⁸ compared to the 97.5% in BRC patients,^3,9 conferring an astronomically high RR of 50-224 for developing BRC in carriers of HLA-A29 versus non-carriers.^4,9 BRC is actually the immunological disease with the strongest HLA association ever described.⁴

Some weaker HLA associations have been reported with other NIU entities, such as HLA-DR4/HLA-DRB1*04 with Vogt-Koyanagi-Harada disease,^10,11 HLA-DRB1*04:05, HLA-DQB1*04:01, and the DRB1*04:05-DQB1*04:01 haplotype with sympathetic ophthalmia,¹² or HLA-DRB1*15:01 and the IL2-RA gene polymorphism rs2104286 A>G with multiple sclerosis-associated uveitis.¹³

In addition to HLA typing and polymorphisms, there has been much interest in evaluating single-nucleotide polymorphisms of various mediators of the immune response. For example, polymorphisms in the ERAP1, ERAP2 or IL-23R genes, have been described in association with uveitis.^14,15 Many other associations have been described.

That being said, the reason why these genetic associations predispose individuals to immunological disease remains a mystery. Some of the hypotheses put forward over the years include interaction of the HLA molecules with the gut microbiome resulting in increased gut permeability and leakage of bacterial products in the circulation, while others think molecular mimicry acting as a trigger for activation of autoreactive lymphocytes specific for the neuroretina might play a role.^16–18

In summary, genetic polymorphisms play a major role in the immunogenetics of some prevalent NIU entities. These may help shape our understanding of pathophysiological mechanisms in the future.

References:

Hou S, Li N, Liao X, Kijlstra A, Yang P. Uveitis genetics. Exp Eye Res. 2020;190:107853. doi:10.1016/j.exer.2019.107853
Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. Eighth edition. Elsevier; 2016.
Kuiper JJ, Prinz JC, Stratikos E, et al. EULAR study group on “MHC-I-opathy”: identifying disease-overarching mechanisms across disciplines and borders. Ann Rheum Dis. 2023;82(7):887-896. doi:10.1136/ard-2022-222852
Feltkamp TE. Ophthalmological significance of HLA associated uveitis. Eye (Lond). 1990;4 (Pt 6):839-844. doi:10.1038/eye.1990.133
Kopplin LJ, Mount G, Suhler EB. Review for Disease of the Year: Epidemiology of HLA-B27 Associated Ocular Disorders. Ocul Immunol Inflamm. 2016;24(4):470-475. doi:10.1080/09273948.2016.1175642
Horie Y, Meguro A, Ohta T, et al. HLA-B51 Carriers are Susceptible to Ocular Symptoms of Behçet Disease and the Association between the Two Becomes Stronger towards the East along the Silk Road: A Literature Survey. Ocul Immunol Inflamm. 2017;25(1):37-40. doi:10.3109/09273948.2015.1136422
Takeno M. The association of Behçet's syndrome with HLA-B51 as understood in 2021. Curr Opin Rheumatol. 2022;34(1):4-9. doi:10.1097/BOR.0000000000000846
Kuiper JJW, Venema WJ. HLA-A29 and Birdshot Uveitis: Further Down the Rabbit Hole. Front Immunol. 2020;11:599558. doi:10.3389/fimmu.2020.599558
Wee R, Papaliodis G. Genetics of Birdshot Chorioretinopathy. Seminars in Ophthalmology. 2008;23(1):53-57. doi:10.1080/08820530701745231
Davis JL, Mittal KK, Freidlin V, et al. HLA associations and ancestry in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Ophthalmology. 1990;97(9):1137-1142. doi:10.1016/s0161-6420(90)32446-6
Shi T, Lv W, Zhang L, Chen J, Chen H. Association of HLA-DR4/HLA-DRB1*04 with Vogt-Koyanagi-Harada disease: a systematic review and meta-analysis. Sci Rep. 2014;4:6887. doi:10.1038/srep06887
Zhao T, Cao Q, Zhou C, Wang Y, Du L, Yang P. Association Between HLA Polymorphisms and Sympathetic Ophthalmia in Han Chinese. Ocul Immunol Inflamm. Published online May 5, 2023:1-8. doi:10.1080/09273948.2023.2205930
Casselman P, Cassiman C, Casteels I, Schauwvlieghe PP. Insights into multiple sclerosis-associated uveitis: a scoping review. Acta Ophthalmol. 2021;99(6):592-603. doi:10.1111/aos.14697
Gelfman S, Monnet D, Ligocki AJ, et al. ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers. Invest Ophthalmol Vis Sci. 2021;62(14):3. doi:10.1167/iovs.62.14.3
Jung JH, Song GG, Kim JH, Seo YH, Choi SJ. The association between genetic polymorphisms of the interleukin-23 receptor gene and susceptibility to uveitis: a meta-analysis. BMC Ophthalmol. 2017;17(1):81. doi:10.1186/s12886-017-0477-4
Rosenbaum JT, Asquith M. The microbiome and HLA-B27-associated acute anterior uveitis. Nat Rev Rheumatol. 2018;14(12):704-713. doi:10.1038/s41584-018-0097-2
Asquith M, Sternes PR, Costello ME, et al. HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome. Arthritis Rheumatol. 2019;71(10):1642-1650. doi:10.1002/art.40917
Horai R, Caspi RR. Microbiome and Autoimmune Uveitis. Front Immunol. 2019;10:232. doi:10.3389/fimmu.2019.00232

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葡萄膜炎是一种多因素疾病，源于我们的基因、环境和随机因素之间的相互作用。要了解葡萄膜炎的免疫遗传学，就必须理解多因素疾病的概念。这些疾病的特点是多基因参与，任何一个变异等位基因既不是发病的必要条件，也不是发病的充分条件。相反，它是多个基因中多个变异的组合，这些变异都会增加个体患某种疾病的易感性。第二个概念是环境诱因，如感染或接触药物，在基因易感个体中引发疾病。随机因素也可能在疾病发生中发挥作用。就葡萄膜炎而言，第一类主要组织相容性复合体（MHC）基因（如 HLA-A 或 HLA-B）的遗传多态性与常见的非感染性葡萄膜炎（NIU）有关，如 HLA-B27 相关急性前葡萄膜炎（AAU）、白塞氏病和鸟枪状视网膜脉络膜炎（BRC）。3 具体来说，HLA-B27携带者在美国高加索人群中的频率约为7%，而在AAU患者中约有50%的携带者，在强直性脊柱炎（AS）患者中约有90%的携带者。这表明，HLA-B27 携带者患 AAU 的相对风险（RR）约为 8，4 而患强直性脊柱炎的相对风险（RR）约为 50 至 100。5 HLA-B51 携带者在丝绸之路沿线人口中的频率约为 10%至 30%，6 而在贝赫切特病患者中的频率为 50%至 80%，因此患该病的 RR 为 5 至 10。与葡萄膜炎相关的第三种主要 HLA 多态性是 HLA-A29，据报道其在西欧人群中的携带率为 5-10%，8 而在白塞氏病患者中的携带率为 97.5%，3,9 因此 HLA-A29 携带者与非携带者相比，患白塞氏病的 RR 高达 50-224。实际上，BRC 是有史以来与 HLA 关联性最强的免疫学疾病。据报道，HLA-DR4/HLA-DRB1*04 与 Vogt-Koyanagi-Harada 病10,11、HLA-DRB1*04:05、HLA-DQB1*04：01、DRB1*04:05-DQB1*04:01 单倍型与交感神经性眼炎12 或 HLA-DRB1*15:01 和 IL2-RA 基因多态性 rs2104286 A>G 与多发性硬化相关性葡萄膜炎。13 除了 HLA 分型和多态性外，人们对评估各种免疫反应介质的单核苷酸多态性也很感兴趣。例如，ERAP1、ERAP2 或 IL-23R 基因的多态性已被描述为与葡萄膜炎有关。尽管如此，这些遗传关联导致个体易患免疫性疾病的原因仍然是个谜。多年来提出的一些假说包括 HLA 分子与肠道微生物群相互作用，导致肠道通透性增加，细菌产物渗漏到血液循环中，而另一些假说则认为分子模拟是激活神经视网膜特异性自反应淋巴细胞的触发因素。16-18 总之，遗传多态性在一些流行的 NIU 实体的免疫遗传学中起着重要作用，这可能有助于我们今后对病理生理机制的理解。参考文献： Hou S, Li N, Liao X, Kijlstra A, Yang P. Uveitis genetics.Exp Eye Res. 2020;190:107853. Doi:10.1016/j.exer.2019.107853 Nussbaum RL, McInnes RR, Willard HF.汤普森与amp；汤普森医学遗传学。第八版。Elsevier; 2016. Kuiper JJ, Prinz JC, Stratikos E, et al. EULAR "MHC-I-opathy "研究小组：跨学科、跨国界的疾病总体机制识别。Ann Rheum Dis.DOI:10.1136/ARD-2022-222852 Feltkamp TE.HLA相关葡萄膜炎的眼科意义。眼（伦敦）。1990; 4 (Pt 6):839-844. Doi:10.1038/eye.1990.133 Kopplin LJ, Mount G, Suhler EB.年度疾病回顾：HLA-B27 相关眼部疾病的流行病学。Ocul Immunol Inflamm.2016;24(4):470-475. doi:10.1080/09273948.2016.1175642 Horie Y, Meguro A, Ohta T, et al. HLA-B51 携带者易患白塞氏病的眼部症状，两者之间的关联在丝绸之路沿线的东方变得更强：文献调查。Ocul Immunol Inflamm.2017;25(1):37-40. doi:10.3109/09273948.2015.

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来源期刊

Acta Ophthalmologica 医学-眼科学

CiteScore

7.60

自引率

5.90%

发文量

433

审稿时长

6 months

期刊介绍： Acta Ophthalmologica is published on behalf of the Acta Ophthalmologica Scandinavica Foundation and is the official scientific publication of the following societies: The Danish Ophthalmological Society, The Finnish Ophthalmological Society, The Icelandic Ophthalmological Society, The Norwegian Ophthalmological Society and The Swedish Ophthalmological Society, and also the European Association for Vision and Eye Research (EVER). Acta Ophthalmologica publishes clinical and experimental original articles, reviews, editorials, educational photo essays (Diagnosis and Therapy in Ophthalmology), case reports and case series, letters to the editor and doctoral theses.