Study explores role of collagen-related genes in central corneal thickness

The genes might govern central corneal thickness and changes in critical ocular structures associated with primary open-angle glaucoma.

Eranga M. Vithana

The presence of two collagen-related genes was strongly associated with central corneal thickness, a major risk factor for glaucoma, in an Asian population, a large study showed.

The findings yielded novel insights into the pathogenesis of glaucoma and abnormalities in corneal tissue, including central corneal thickness (CCT), Eranga M. Vithana, PhD, the study’s corresponding author, told Ocular Surgery News in an email interview.

“Genes that either encode collagens or genes that may control the expression of collagen genes are important for CCT control, but this is not surprising considering that collagens are essential components of corneal stroma,” Dr. Vithana said. “It also seems that rare severe mutations in collagen genes result in extreme phenotypes, while milder variants in the same genes are associated with normal variations of CCT.”

The population-based genome-wide association study on CCT, the first such investigation conducted in Asia, was jointly conducted by scientists from the Singapore Eye Research Institute (SERI), the National University of Singapore (NUS), Genome Institute of Singapore (GIS), an institute of Singapore’s Agency of Science, Technology and Research (A*STAR) and the Duke-NUS Graduate Medical School in Singapore. It included subjects of Malay and Indian descent drawn from these two ethnic populations in Singapore via the SERI-led landmark, community-based studies that systematically documented the frequency, causes and impact of low vision and major eye diseases in the different racial and ethnic groups in Singapore.

Results were published in Human Molecular Genetics.

The results did not demonstrate direct associations between CCT and primary open-angle glaucoma but may shed light on how collagen genes influence various ocular structures, Dr. Vithana said.

“There is no basic pathway as such,” she said. “The relationship is likely to be complex, and we hypothesize that some of the collagen genes that control the normal variation of central corneal thickness also play a role in tissues relevant to glaucoma, such as the optic nerve head and trabecular meshwork. It is possible that certain alleles of collagen genes are expressed aberrantly when the tissue is subjected to the stresses associated with high IOP.”

The findings may lead to genetic testing methods for glaucoma in the future, Dr. Vithana said.

“By identifying genes that control CCT, which is a risk factor for primary open-angle glaucoma, we are getting closer to identifying genes for glaucoma itself and will one day be able to predict who is at risk of this major eye disease,” she said.

Genotyping, clinical testing

The study combined data from the Singapore Indian Eye Study (SINDI), which included 2,538 Indian subjects, and the Singapore Malay Eye Study (SiMES), which included 2,542 Malay subjects. All subjects were at least 40 years old.

Subjects underwent five CCT measurements in each eye taken with the Advent ultrasound pachymeter (Mentor O&O). Readings from the right eye were included in the analysis.

All subjects were genotyped. Quality control analysis was performed with a single nucleotide polymorphism (SNP) test.

In both the SiMES and SINDI studies, some subjects were excluded because of evidence of genetic admixture, gender discrepancies, cryptic relatedness, or impossible biological sharing or heterogeneity.

The SiMES study included 557,824 SNPs; the SINDI study included 559,119 SNPs.

Novel genetic loci

Investigators identified two genetic loci associated with CCT: 1p34.3 near COL8A2 and 9q34 at the intersection between RXRA and COL5A1. Data also confirmed an association at the ZNF469 gene.

A novel cluster of SNPs on chromosome 1p34.3 upstream from the collagen VIII alpha 2 gene strongly suggested an association with CCT in the SINDI cohort.

In SINDI, single-locus analysis showed the strongest evidence of an association with CCT with a cluster of SNPs on chromosome 16q24 near the ZNF469 gene. The most significant SNP was rs9938149. The presence of each copy of the minor allele of rs9938149 correlated with a 6.29-µm decrease in CCT, suggesting an effect on intracorneal tissue.

The collagen gene COL8A2 is expressed in other tissues associated with glaucoma, such as the optic nerve head and optic disc. Rare COL8A2 mutations have been identified in some glaucoma patients with CCT of less than 530 µm.

A meta-analysis of SINDI and SiMES suggested an association with CCT exceeding the genome-wide significance at the interval between RXRA and COL5A1.

Data showed ZNF469 as an important locus for CCT in Asians and individuals of European descent, the authors said. – by Matt Hasson

Reference:

• Vithana EN, Aung T, Khor CC, et al. Collagen-related genes influence the glaucoma risk factor, central corneal thickness. Hum Mol Genet. 2011;20(4):649-658.

• Eranga N. Vithana, PhD, can be reached at Singapore Eye Research Institute, 11 Third Hospital Avenue 06-35, Singapore 168751; +65-6322-4542; fax: +65-6322-4599; email: eranga.n.v@seri.com.sg.
• Disclosure: Dr. Vithana has no direct financial interest in the products discussed in this article, nor is she a paid consultant for any companies mentioned.