Findings point to potential risk prediction tool
March 30, 2017
NEI
Corneal section from a person with Fuchs dystrophy shows the presence of ATP1B1 in the corneal endothelium.

Corneal section from a person with Fuchs dystrophy shows the presence of ATP1B1 in the corneal endothelium.

An international study of more than 5,417 people helps pinpoint the genetic risk factors associated with Fuchs endothelial corneal dystrophy, the most common disorder requiring corneal transplantation. The discovery of gene variants illuminates the biological mechanisms for the disorder, which affects 4 percent of people age 40 and older. The study appears in Nature Communications and was funded by the National Eye Institute, part of the National Institutes of Health.

Researchers from 16 collaborating study sites compared genomic data from 2,075 people with and 3,342 without Fuchs dystrophy. Analyses found novel associations with three loci—regions of the genetic code—and the disorder at genes KANK4, LAMC1 and ATP1B1. These loci had not been linked previously to Fuchs or other corneal dystrophies. In addition, they confirmed the relevance of a fourth locus at the gene TCF4, which had been linked to Fuchs dystrophy in earlier studies.

Importantly, the investigators detected the first known sex-specific genetic association with Fuchs dystrophy. Specifically, they found that LAMC1 variants confer a significantly elevated risk of Fuchs dystrophy among women, while TCF4 variants confer a greater risk in men.

Together the four loci predict the risk of an individual developing Fuchs dystrophy with an accuracy of about 78 percent, said one of the study’s lead authors, Sudha K Iyengar, Ph.D., Case Western Reserve University, Cleveland. “Considering that there is currently no clinical screening tool other than family history, this is a significant advance for development of molecular diagnostic tests,” she said.“The identification of these genes paves the way for the development of a test to identify individuals who are at risk of getting Fuchs dystrophy, and also for the development of drugs to slow disease progression or to potentially delay or prevent it from occurring,” said George A. McKie, D.V.M., PhD., director of the NEI’s cornea research program.

Corneal sections from a person with Fuchs dystrophy (left), normal with staining (center), and normal no staining (right)

Corneal sections from a person with Fuchs dystrophy (left) show the presence of ATP1B1 in the corneal endothelium. Findings were similar for the normal control (center). The negative control (with no staining for antibodies to ATP1B1) is shown right. Photos courtesy of Sudha K Iyengar, Ph.D.

Fuchs dystrophy is a progressive disease that affects the clear covering of the eye called the cornea. Affecting both eyes, Fuchs occurs when cells die in the endothelium, the innermost layer of the cornea, and the body fails to replace them. Death of corneal endothelial cells is a normal part of aging, however, Fuchs accelerates this cell death, Iyengar said.

The endothelium’s primary task is to pump excess fluid out of the cornea to keep hydration levels optimal. Under normal conditions, fluid from the center of the eye slowly leaks into the outer layers of cornea and is pumped back into the eye by a healthy endothelium. As the endothelium layer dies, fluid accumulates in the central or stromal layer of the cornea leading to edema or swelling. This edema causes people in the early stages of Fuchs dystrophy to wake up with blurry vision that resolves later in the day once the cornea dries. As the disease progresses, painful erosions and blisters form within the corneal layers and the ability to focus sharply is permanently lost.  

Early in the disease, people can manage their symptoms by pointing a hairdryer at their eyes at arm’s length to accelerate drying the corneal surface. Such strategies no longer work as the disease progresses. Eventually a corneal transplant—most often from a deceased organ donor—is necessary.  

The investigators confirmed the activity of genes at the newly identified loci by probing discarded corneal tissue from deceased individuals with and without Fuchs. They also used immunohistochemistry to look at protein expression from living people with Fuchs using the part of the cornea that is removed during the transplant procedure. Based on studies of other tissues, the genes very well could play an essential role in the health of the corneal endothelium, according to the study authors. “Disruption of these activities could conceivably lead to Fuchs,” Iyengar said. For example, ATP1B1 encodes a sub-unit of the sodium-potassium plasma membrane pump, which is essential for water and ion transport. In other cases, the genes were found to be vital for the maintenance of membranes, tissue integrity and cell-to-cell contact. 

Future studies will investigate the role of these genes in the underlying biology of Fuchs dystrophy.

This work was funded in part by NEI grants R01 EY023196, R01 EY016482, R01 EY016514, R01 EY016835, R21 EY015145 and P30 EY11373.

Reference: Natalie A. Afshari, “Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy” Nature Communications, March 30, 2017, DOI:10.1038/NCOMMS14898 Pubmed

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