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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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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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.</description><identifier>ISSN: 1552-5783</identifier><identifier>ISSN: 0146-0404</identifier><identifier>EISSN: 1552-5783</identifier><identifier>DOI: 10.1167/iovs.65.12.32</identifier><identifier>PMID: 39436372</identifier><language>eng</language><publisher>United States: The Association for Research in Vision and Ophthalmology</publisher><subject>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</subject><ispartof>Investigative ophthalmology & visual science, 2024-10, Vol.65 (12), p.32</ispartof><rights>Copyright 2024 The Authors 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c235t-4130a09a03bcb9d727d4dd05876c055325fb7a268e18be75e4f83c2b3b72b20f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500050/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500050/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39436372$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cerván-Martín, Miriam</creatorcontrib><creatorcontrib>Higueras-Serrano, Inmaculada</creatorcontrib><creatorcontrib>González-Muñoz, Sara</creatorcontrib><creatorcontrib>Guzmán-Jiménez, Andrea</creatorcontrib><creatorcontrib>Chaves-Urbano, Blas</creatorcontrib><creatorcontrib>Palomino-Morales, Rogelio J</creatorcontrib><creatorcontrib>Poo-López, Arancha</creatorcontrib><creatorcontrib>Fernández-Vega-Cueto, Luis</creatorcontrib><creatorcontrib>Merayo-Lloves, Jesús</creatorcontrib><creatorcontrib>Alcalde, Ignacio</creatorcontrib><creatorcontrib>Bossini-Castillo, Lara</creatorcontrib><creatorcontrib>Carmona, F David</creatorcontrib><title>Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation</title><title>Investigative ophthalmology & visual science</title><addtitle>Invest Ophthalmol Vis Sci</addtitle><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.</description><subject>Adult</subject><subject>Female</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genotype</subject><subject>Humans</subject><subject>Keratoconus - diagnosis</subject><subject>Keratoconus - drug therapy</subject><subject>Keratoconus - genetics</subject><subject>Male</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Translational Research, Biomedical</subject><issn>1552-5783</issn><issn>0146-0404</issn><issn>1552-5783</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1PwzAMhiME4vvIFeXIpSMfTdNyQTCNgUDAYZyjNHW3oDYZSTvEv6djgEA-2LIfv7b0InRCyYjSTJ5bv4qjTIwoG3G2hfapECwRMufbf-o9dBDjKyGMUkZ20R4vUp5xyfbRfOzbZYAFuGhXgCcr3fS6s95hX-NuAXgKDjpr8LWONq6b9xB05413fbzAj_COnyHEJZhu2I-49gGPG-us0Q2eBe1i8yV3hHZq3UQ4_s6H6OVmMhvfJg9P07vx1UNiGBddklJONCk04aUpi0oyWaVVRUQuM0OE4EzUpdQsy4HmJUgBaZ1zw0peSlYyUvNDdLnRXfZlC5UB1wXdqGWwrQ4fymur_k-cXai5XylKBSFEkEHh7Fsh-LceYqdaGw00jXbg-6g4pcUQPJUDmmxQE3yMAerfO5SotTtq7Y7KhKJMcTbwp3-f-6V_7OCfLdGNvQ</recordid><startdate>20241001</startdate><enddate>20241001</enddate><creator>Cerván-Martín, Miriam</creator><creator>Higueras-Serrano, Inmaculada</creator><creator>González-Muñoz, Sara</creator><creator>Guzmán-Jiménez, Andrea</creator><creator>Chaves-Urbano, Blas</creator><creator>Palomino-Morales, Rogelio J</creator><creator>Poo-López, Arancha</creator><creator>Fernández-Vega-Cueto, Luis</creator><creator>Merayo-Lloves, Jesús</creator><creator>Alcalde, Ignacio</creator><creator>Bossini-Castillo, Lara</creator><creator>Carmona, F David</creator><general>The Association for Research in Vision and Ophthalmology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20241001</creationdate><title>Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c235t-4130a09a03bcb9d727d4dd05876c055325fb7a268e18be75e4f83c2b3b72b20f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adult</topic><topic>Female</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetics</topic><topic>Genome-Wide Association Study</topic><topic>Genotype</topic><topic>Humans</topic><topic>Keratoconus - diagnosis</topic><topic>Keratoconus - drug therapy</topic><topic>Keratoconus - genetics</topic><topic>Male</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Translational Research, Biomedical</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cerván-Martín, Miriam</creatorcontrib><creatorcontrib>Higueras-Serrano, Inmaculada</creatorcontrib><creatorcontrib>González-Muñoz, Sara</creatorcontrib><creatorcontrib>Guzmán-Jiménez, Andrea</creatorcontrib><creatorcontrib>Chaves-Urbano, Blas</creatorcontrib><creatorcontrib>Palomino-Morales, Rogelio J</creatorcontrib><creatorcontrib>Poo-López, Arancha</creatorcontrib><creatorcontrib>Fernández-Vega-Cueto, Luis</creatorcontrib><creatorcontrib>Merayo-Lloves, Jesús</creatorcontrib><creatorcontrib>Alcalde, Ignacio</creatorcontrib><creatorcontrib>Bossini-Castillo, Lara</creatorcontrib><creatorcontrib>Carmona, F David</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Investigative ophthalmology & visual science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cerván-Martín, Miriam</au><au>Higueras-Serrano, Inmaculada</au><au>González-Muñoz, Sara</au><au>Guzmán-Jiménez, Andrea</au><au>Chaves-Urbano, Blas</au><au>Palomino-Morales, Rogelio J</au><au>Poo-López, Arancha</au><au>Fernández-Vega-Cueto, Luis</au><au>Merayo-Lloves, Jesús</au><au>Alcalde, Ignacio</au><au>Bossini-Castillo, Lara</au><au>Carmona, F David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation</atitle><jtitle>Investigative ophthalmology & visual science</jtitle><addtitle>Invest Ophthalmol Vis Sci</addtitle><date>2024-10-01</date><risdate>2024</risdate><volume>65</volume><issue>12</issue><spage>32</spage><pages>32-</pages><issn>1552-5783</issn><issn>0146-0404</issn><eissn>1552-5783</eissn><abstract>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.</abstract><cop>United States</cop><pub>The Association for Research in Vision and Ophthalmology</pub><pmid>39436372</pmid><doi>10.1167/iovs.65.12.32</doi><oa>free_for_read</oa></addata></record> |
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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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