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

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 di...

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Veröffentlicht in:Investigative ophthalmology & visual science 2024-10, Vol.65 (12), p.32
Hauptverfasser: Cerván-Martín, Miriam, Higueras-Serrano, Inmaculada, González-Muñoz, Sara, Guzmán-Jiménez, Andrea, Chaves-Urbano, Blas, Palomino-Morales, Rogelio J, Poo-López, Arancha, Fernández-Vega-Cueto, Luis, Merayo-Lloves, Jesús, Alcalde, Ignacio, Bossini-Castillo, Lara, Carmona, F David
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container_end_page
container_issue 12
container_start_page 32
container_title Investigative ophthalmology & visual science
container_volume 65
creator Cerván-Martín, Miriam
Higueras-Serrano, Inmaculada
González-Muñoz, Sara
Guzmán-Jiménez, Andrea
Chaves-Urbano, Blas
Palomino-Morales, Rogelio J
Poo-López, Arancha
Fernández-Vega-Cueto, Luis
Merayo-Lloves, Jesús
Alcalde, Ignacio
Bossini-Castillo, Lara
Carmona, F David
description 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. 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. 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. 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.
doi_str_mv 10.1167/iovs.65.12.32
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subjects Adult
Female
Genetic Predisposition to Disease
Genetics
Genome-Wide Association Study
Genotype
Humans
Keratoconus - diagnosis
Keratoconus - drug therapy
Keratoconus - genetics
Male
Polymorphism, Single Nucleotide
Translational Research, Biomedical
title Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation
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