Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation.

IF 5 2区 医学 Q1 OPHTHALMOLOGY
Miriam Cerván-Martín, Inmaculada Higueras-Serrano, Sara González-Muñoz, Andrea Guzmán-Jiménez, Blas Chaves-Urbano, Rogelio J Palomino-Morales, Arancha Poo-López, Luis Fernández-Vega-Cueto, Jesús Merayo-Lloves, Ignacio Alcalde, Lara Bossini-Castillo, F David Carmona
{"title":"Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation.","authors":"Miriam Cerván-Martín, Inmaculada Higueras-Serrano, Sara González-Muñoz, Andrea Guzmán-Jiménez, Blas Chaves-Urbano, Rogelio J Palomino-Morales, Arancha Poo-López, Luis Fernández-Vega-Cueto, Jesús Merayo-Lloves, Ignacio Alcalde, Lara Bossini-Castillo, F David Carmona","doi":"10.1167/iovs.65.12.32","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Keratoconus (KC) is a corneal disorder with complex etiology, apparently involving both genetic and environmental factors, characterized by progressive thinning and protrusion of the cornea. We aimed to identify novel genetic regions associated with KC susceptibility, elucidate relevant genes for disease development, and explore the translational implications for therapeutic intervention and risk assessment.</p><p><strong>Methods: </strong>We conducted a genome-wide association study (GWAS) that integrated previously published data with newly generated genotyping data from an independent European cohort. To evaluate the clinical translation of our results, we performed functional annotation, gene prioritization, polygenic risk score (PRS), and drug repositioning analyses.</p><p><strong>Results: </strong>We identified two novel genetic loci associated with KC, with rs2806689 and rs807037 emerging as lead variants (P = 1.71E-08, odds ratio [OR] = 0.88; P = 1.93E-08, OR = 1.16, respectively). Most importantly, we identified 315 candidate genes influenced by confirmed KC-associated variants. Among these, MINK1 was found to play a pivotal role in KC pathogenesis through the WNT signaling pathway. Moreover, we developed a PRS model that successfully differentiated KC patients from controls (P = 7.61E-16; area under the curve = 0.713). This model has the potential to identify individuals at high risk for developing KC, which could be instrumental in early diagnosis and management. Additionally, our drug repositioning analysis identified acetylcysteine as a potential treatment option for KC, opening up new avenues for therapeutic intervention.</p><p><strong>Conclusions: </strong>Our study provides valuable insights into the genetic and molecular basis of KC, offering new targets for therapy and highlighting the clinical utility of PRS models in predicting disease risk.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500050/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Investigative ophthalmology & visual science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1167/iovs.65.12.32","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Purpose: Keratoconus (KC) is a corneal disorder with complex etiology, apparently involving both genetic and environmental factors, characterized by progressive thinning and protrusion of the cornea. We aimed to identify novel genetic regions associated with KC susceptibility, elucidate relevant genes for disease development, and explore the translational implications for therapeutic intervention and risk assessment.

Methods: We conducted a genome-wide association study (GWAS) that integrated previously published data with newly generated genotyping data from an independent European cohort. To evaluate the clinical translation of our results, we performed functional annotation, gene prioritization, polygenic risk score (PRS), and drug repositioning analyses.

Results: We identified two novel genetic loci associated with KC, with rs2806689 and rs807037 emerging as lead variants (P = 1.71E-08, odds ratio [OR] = 0.88; P = 1.93E-08, OR = 1.16, respectively). Most importantly, we identified 315 candidate genes influenced by confirmed KC-associated variants. Among these, MINK1 was found to play a pivotal role in KC pathogenesis through the WNT signaling pathway. Moreover, we developed a PRS model that successfully differentiated KC patients from controls (P = 7.61E-16; area under the curve = 0.713). This model has the potential to identify individuals at high risk for developing KC, which could be instrumental in early diagnosis and management. Additionally, our drug repositioning analysis identified acetylcysteine as a potential treatment option for KC, opening up new avenues for therapeutic intervention.

Conclusions: Our study provides valuable insights into the genetic and molecular basis of KC, offering new targets for therapy and highlighting the clinical utility of PRS models in predicting disease risk.

全面评估角膜病的遗传基础:临床转化的新视角。
目的:角膜炎(KC)是一种病因复杂的角膜疾病,显然涉及遗传和环境因素,其特征是角膜逐渐变薄和突出。我们的目的是确定与 KC 易感性相关的新基因区域,阐明疾病发展的相关基因,并探索其对治疗干预和风险评估的转化意义:我们进行了一项全基因组关联研究(GWAS),该研究整合了以前发表的数据和一个独立欧洲队列中新生成的基因分型数据。为了评估研究结果的临床转化,我们进行了功能注释、基因优先排序、多基因风险评分(PRS)和药物重新定位分析:结果:我们发现了两个与 KC 相关的新基因位点,其中 rs2806689 和 rs807037 为先导变异(P = 1.71E-08,几率比 [OR] = 0.88;P = 1.93E-08,OR = 1.16)。最重要的是,我们发现了 315 个受已证实的 KC 相关变异影响的候选基因。其中,MINK1 被发现通过 WNT 信号通路在 KC 发病机制中发挥关键作用。此外,我们还建立了一个 PRS 模型,成功地将 KC 患者与对照组区分开来(P = 7.61E-16;曲线下面积 = 0.713)。该模型有望识别出罹患 KC 的高危人群,从而有助于早期诊断和治疗。此外,我们的药物重新定位分析发现乙酰半胱氨酸是治疗 KC 的潜在选择,为治疗干预开辟了新途径:我们的研究为 KC 的遗传和分子基础提供了宝贵的见解,为治疗提供了新的靶点,并突出了 PRS 模型在预测疾病风险方面的临床实用性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
6.90
自引率
4.50%
发文量
339
审稿时长
1 months
期刊介绍: Investigative Ophthalmology & Visual Science (IOVS), published as ready online, is a peer-reviewed academic journal of the Association for Research in Vision and Ophthalmology (ARVO). IOVS features original research, mostly pertaining to clinical and laboratory ophthalmology and vision research in general.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信