BLOG: Genetic research will elevate understanding of keratoconus
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The National Institutes of Health says that most diseases, except trauma-based conditions, have a genetic determinant. Keratoconus is no exception.
I first heard that keratoconus (KC) was possibly linked to genetics about 20 years ago from Yaron Rabinowitz, MD, of Cedars Sinai Medical Center in Los Angeles. At the time I was skeptical but fascinated by the possibility that there was a root cause for the disease. I became passionate about managing KC with specialty lenses, corneal transplant comanagement and family counseling.
In the late 1990s, the hope that we might predict KC risk based on family history empowered us to tell possibly susceptible family members to not rub their eyes and to avoid corneal refractive surgery. My interest in KC led to work with Dr. Rabinowitz and others, resulting in an acceleration of discoveries in the field of genomic determinants of KC.
It makes sense that KC is at least partially inherited given the evidence in the literature. In twin studies, there is a higher concordance of KC in monozygotic than in dizygotic twins (Loukovitis et al). There is an association with other known genetic conditions, including Down syndrome with an estimated prevalence of 5.5% (Kristianslund and Drolsum). Connective tissue disorders are over-represented among patients with KC, suggesting underlying structural abnormalities. Having a first-degree relative with KC remains the most significant risk factor (Wang et al).
Genome-wide association studies (GWAS) of KC cases and population-wide studies of variation in central corneal thickness and corneal biomechanical properties have confirmed already identified genes and have found new susceptibility variants (Bykhovskaya and Rabinowitz). Collaborative research has identified more than three dozen new or confirmed genes involved in the genetic susceptibility of KC (Hardcastle et al.). Almost 100 genomic loci have been identified as associated with central corneal thickness, and more than 200 related loci are associated with corneal biomechanical properties.
Although there are hundreds of genes related to central corneal thickness and corneal biomechanics, only a few dozen are associated with KC. Importantly, those common genes are consistently related to collagen and extracellular matrix regulation as main pathways of tissue change.
Studies of genetic variation in KC (or any disease for that matter) take thousands of patients with and without the disease to uncover genetic pathways. A 2021 GWAS by Hardcastle and colleagues — that is the largest GWAS related to KC performed to date — examined 4,669 cases and 116,547 controls. In that study, the common variants found to be associated with KC explained 12.5% of overall KC heritability, implying potential for the development of an accurate diagnostic test to detect susceptibility to disease. However, we are not there yet. Even larger studies are required to identify the remaining genetic risk for this condition.
Identification of genetic risk factors has enhanced our understanding of this corneal disease and points to poor regulation of connective tissue homeostasis. A more complete understanding of the link between genetics and KC risk may allow targeting specific patients and the development of novel therapies.
For example, an accurate genetic test could assist us in identifying individuals in whom corneal collagen cross-linking would be an effective means of arresting disease progression. This would be an enormous step toward the implementation of genomic medicine into clinical practice.
References:
- Bykhovskaya Y, Rabinowitz YS. Exp Eye Res. 2021;doi:10.1016/j.exer.2020.108398.
- Hardcastle AJ, et al. Commun Biol. 2021;doi:10.1038/s42003-021-01784-0.
- Kristianslund O, Drolsum L. JAMA Netw Open. 2021;doi:10.1001/jamanetworkopen.2021.0814.
- Loukovitis E, et al. Ophthalmol Ther. 2018;doi:10.1007/s40123-018-0144-8.
- National Institutes of Health. National Human Genome Research Institute. Genetic Disorders. Accessed: April 13, 2021. Updated May 18, 2018. https://www.genome.gov/For-Patients-and-Families/Genetic-Disorders.
- Wang Y, et al. Am J Med Genet. 2000;doi:10.1002/1096-8628(20000828)93:5<403::AID-AJMG11>3.0.CO;2-A.
Loretta Szczotka-Flynn, OD, PhD, is a professor in the Case Western Reserve University Departments of Ophthalmology & Visual Sciences as well as Population & Quantitative Health Sciences. She is director of the Contact Lens Service at the University Hospitals Eye Institute in Cleveland, Ohio.
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