New study quadruples known genetic risk factors for Fuchs dystrophy

April 11, 2017, Case Western Reserve University

Researchers discovered three novel genetic mutations associated with Fuchs endothelial corneal dystrophy, the most common corneal disorder requiring transplantation.

The study is published in Nature Communications. Sudha K. Iyengar, PhD, Professor of Epidemiology and Biostatistics, Vice Chair for Research at Case Western Reserve University School of Medicine, and member of the Case Comprehensive Cancer Center in Cleveland, Ohio is the lead author.

Corneal diseases are common causes of blindness worldwide. One highly heritable disease, Fuchs , causes painful corneal swelling and blurred vision. The disease commonly requires corneal transplant from a deceased donor. Approximately 4% of United States adults age 40 and older develop Fuchs dystrophy.

Only one gene—TCF4—has been successfully associated with Fuchs dystrophy in genetic studies. Iyengar and her team set out to perform the largest genetic scan to date for the disease, to identify other that could inform treatment efforts.

An international team of 36 researchers compared DNA sequences from 2,075 people with Fuchs dystrophy and 3,342 without the disease. They generated a list of 18 genetic variations found only in people with Fuchs dystrophy, later narrowing the list to three most relevant to disease with the help of corneal laboratory models.

The team spanned 16 institutions and included first authors Robert Igo, PhD, Assistant Professor of Epidemiology and Biostatistics at Case Western Reserve University School of Medicine and Natalie Afshari, MD, FACS, Professor of Opthalmology at University of California San Diego. Iyengar led the study alongside Yi-Ju Li, PhD, Associate Professor at Duke University School of Medicine, and Jonathan Lass, MD, Charles I Thomas Professor of Ophthalmology and Visual Sciences at Case Western Reserve University School of Medicine.

The study revealed three novel variations in the human genome that increase risk of Fuchs dystrophy. The variations—KANK4, LAMC1, and ATP1B1—have never before been associated with Fuchs dystrophy. The new study quadruples the number of known genetic risk factors for Fuchs dystrophy, and helps explain its genetic etiology.

The researchers also discovered the first sex-specific differences in Fuchs dystrophy genetics. They found men with a specific variation in the well-known TCF4 gene have a higher risk of disease, while women with variations in one of the newly identified genes, LAMC1, have an increased risk. The genes can help predict a person's risk of developing disease with approximately 78% accuracy, and could be targeted by molecular diagnostic tests.

"In most individuals with Fuchs Endothelial Corneal Dystrophy (FECD) the cause of the disease is unknown. It was thought that genetics only played a role in those with a of FECD. Our results pointed to three new genetic markers for FECD and confirmed the vital role of a previously known marker even among those who did not have a previously known family history of the disease. Thus, our work showed that knowing the genetic architecture is key to understanding this disease," Iyengar said.

"The markers we identified can be used to develop a biomarker panel for pre-symptomatic testing even among people who did not have a family history," Iyengar indicated.

"The cornea is the clear tissue in the front of the eye that lets light into the eye so we can see. FECD is the most common reason older individuals get a when their cornea starts to loses transparency," explained Iyengar. "There is no cure other than surgery. Therefore, other ways to help cure this disease are necessary as the US population gets older.

"Considering that there is currently no clinical screening tool other than family history, this is a significant advance for development of molecular diagnostic tests," Iyengar said.

The researchers used corneal tissue samples to identify biologic roles for the new genes. While their preliminary experiments suggest the genes help control fluid levels in the cornea, Iyengar cautions that additional laboratory models will be needed to pinpoint their precise functions.

Explore further: Researchers find new genetic links underlying progressively blinding eye disease

More information: Natalie A. Afshari et al, Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy, Nature Communications (2017). DOI: 10.1038/ncomms14898

Related Stories

Researchers find new genetic links underlying progressively blinding eye disease

March 31, 2017
Corneal diseases are among the most common causes of visual impairment and blindness, with Fuchs endothelial corneal dystrophy (FECD), a gradual swelling and clouding of the cornea, being the most common reason for eventual ...

Corneal thickness linked to early stage Fuchs' Endothelial Corneal Dystrophy

April 9, 2012
A national consortium of researchers has published new findings that could change the standard of practice for those treating Fuchs' Endothelial Corneal Dystrophy (FECD), a disease characterized by cornea swelling that can ...

Researchers find proliferating cells in normal and diseased corneal endothelium

September 14, 2016
Researchers from Massachusetts Eye and Ear have, for the first time, identified rapidly proliferating cells (known as "neural crest-derived progenitor cells") in the corneal endothelium of specimens from normal corneas and ...

New research links mitochondrial dysfunction to the development of FECD

March 3, 2016
Researchers at Schepens Eye Research Institute of Massachusetts Eye and Ear have shown a link between mitochondrial dysfunction in corneal endothelial cells and the development of Fuchs' Endothelial Corneal Dystrophy. This ...

Study confirms genetic predictor for Fuchs' corneal dystrophy

May 7, 2012
Mayo Clinic and University of Oregon researchers have confirmed that a genetic factor called a repeating trinucleotide is a strong predictor of an individual's risk of developing the eye condition Fuchs' dystrophy. The findings ...

Corneal transplants, men and women don't see eye to eye

July 14, 2016
A new study of patients undergoing corneal transplants indicates that subtle differences between men and women may lead to poorer outcomes for a woman who has received a cornea from a male donor.

Recommended for you

Natural barcodes enable better cell tracking

April 24, 2018
Each of us carries in our genomes about 10 million genetic variations called single nucleotide polymorphisms (SNPs), which represent a difference of just one letter in the genetic code. Every human's pattern of SNPs is unique ...

The role of 'extra' DNA in cancer evolution and therapy resistance

April 23, 2018
Glioblastoma (GBM) is the most common and aggressive form of brain cancer. Response to standard-of-care treatment is poor, with a two-year survival rate of only 15 percent. Research is beginning to provide a better understanding ...

Variants in non-coding DNA contribute to inherited autism risk

April 19, 2018
In recent years, researchers have firmly established that gene mutations appearing for the first time, called de novo mutations, contribute to approximately one-third of cases of autism spectrum disorder (ASD). In a new study, ...

Researchers discover link between gene variation and language

April 18, 2018
What shapes the basic features of a language?

Natural selection still at work in humans

April 18, 2018
Evolution has shaped the human race, with University of Queensland researchers finding signatures of natural selection in the genome that influence traits associated with fertility and heart function.

Gene therapy for beta-thalassemia safe, effective in people

April 18, 2018
In a powerful example of bench-to-bedside science showing how observations made in the lab can spark life-altering therapies in clinic, an international team of clinician-investigators has announced that gene therapy for ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.