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A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

ABSTRACT: Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

SUBMITTER: Hardcastle AJ

PROVIDER: S-EPMC7921564 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

Hardcastle Alison J AJ Liskova Petra P Bykhovskaya Yelena Y McComish Bennet J BJ Davidson Alice E AE Inglehearn Chris F CF Li Xiaohui X Choquet Hélène H Habeeb Mahmoud M Lucas Sionne E M SEM Sahebjada Srujana S Pontikos Nikolas N Lopez Karla E Rojas KER Khawaja Anthony P AP Ali Manir M Dudakova Lubica L Skalicka Pavlina P Van Dooren Bart T H BTH Geerards Annette J M AJM Haudum Christoph W CW Faro Valeria Lo VL Tenen Abi A Simcoe Mark J MJ Patasova Karina K Yarrand Darioush D Yin Jie J Siddiqui Salina S Rice Aine A Farraj Layal Abi LA Chen Yii-Der Ida YI Rahi Jugnoo S JS Krauss Ronald M RM Theusch Elisabeth E Charlesworth Jac C JC Szczotka-Flynn Loretta L Toomes Carmel C Meester-Smoor Magda A MA Richardson Andrea J AJ Mitchell Paul A PA Taylor Kent D KD Melles Ronald B RB Aldave Anthony J AJ Mills Richard A RA Cao Ke K Chan Elsie E Daniell Mark D MD Wang Jie Jin JJ Rotter Jerome I JI Hewitt Alex W AW MacGregor Stuart S Klaver Caroline C W CCW Ramdas Wishal D WD Craig Jamie E JE Iyengar Sudha K SK O'Brart David D Jorgenson Eric E Baird Paul N PN Rabinowitz Yaron S YS Burdon Kathryn P KP Hammond Chris J CJ Tuft Stephen J SJ Hysi Pirro G PG

Communications biology 20210301 1

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci ...[more]

PMID: 33649486

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Project description:Keratoconus (KC) is a progressive corneal ectasia linked to thinning of the central cornea. Hard contact lenses, rigid gas permeable lenses, and scleral lenses are the primary treatment modalities for early to mid- stages of KC to correct refractive error and astigmatism that develops as a result of an irregular corneal structure. These treatments are associated with significant drawbacks, including reduced availability of the tear film and oxygen to the corneal epithelium and stroma. However, it remains unknown whether hypoxia affects corneal integrity in the KC pathobiology. A number of studies have associated elevated oxidative stress with KC both in vitro and ex vivo. We hypothesized that KC-derived corneal fibroblasts are more susceptible to hypoxia-induced oxidative stress compared to healthy controls leading to exacerbation of corneal thinning in KC. This study investigated the effects of hypoxia on ECM secretion, assembly, and matrix metalloproteinase (MMP) expression in human corneal fibroblasts from healthy controls (HCFs) and KC patients (HKCs) in vitro. HCFs and HKCs were cultured in 3D constructs for 3 weeks and maintained or transferred to normoxic (21% O2) or hypoxic (2% O2) conditions, respectively, for 1 additional week. At the 4 week time-point, constructs were isolated and probed for Collagen I, III, and V, keratocan and MMP-1, -2, -3, -9, and -13, as well as hypoxia markers, hypoxia inducible factor-1α and lactoferrin. Conditioned media was also collected and probed for Collagen I, III, and V by Western blot. Thickness of the ECM assembled by HCFs and HKCs was measured using immunofluorescence microscopy. Results showed that hypoxia significantly reduced Collagen I secretion in HKCs, as well as upregulated the expression of MMP-1 and -2 with no significant effects on MMP-3, -9, or -13. ECM thickness was reduced in both cell types following 1 week in a low oxygen environment. Our study shows that hypoxia influences collagen and MMP expression by HKCs, which may have consequential effects on ECM structure in the context of KC.

Dataset Information

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

Publications

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

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