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Study links three genes to optic disc area in disparate populations
Further research on genetic determinants could illuminate glaucoma pathogenesis and spur novel treatments.
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Genome-wide association studies pinpointed genetic factors that govern optic disc area in Asian and Caucasian populations, researchers reported.
An Asian-based association study on optic disc area identified a novel gene in Asians, while a similar analysis identified two other genes in Europeans. The presence of all three genes has been confirmed in both populations.
“Three genes were unequivocally associated with optic disc area,” Tin Aung, MBBS, N/MEd (Ophth), FRCS (Ed), FRCOphth, FAMS, PhD, OSN APAO Edition Board Member, told Ocular Surgery News in an email interview.
“Two of them, ATOH7 and TGFBR3, have been shown in Europeans, and the third, CARD10, is newly identified in Asians and subsequently confirmed in Europeans,” Dr. Aung, the study’s corresponding author, said.
Anatomic similarities suggest genetic common denominators across the Asian and European cohorts, Dr. Aung said.
“The genes are similarly associated with optic disc size, as all three were common and shared across Asians and Europeans,” he said. “The eye structures are very similar, with average disc sizes very similar between the Asian and European cohorts.”
The optic disc is the site where ganglion cell axons egress the eye to form the optic nerve. Previous research has suggested that larger optic disc area might be associated with glaucoma.
Further research on genetic determinants could yield deeper insight into disease pathogenesis and spur novel glaucoma treatments, Dr. Aung said.
“In the long term, we may be better able to understand the mechanisms of disease for glaucoma,” he said.
Results were published in Human Molecular Genetics.
Methods and findings
Dr. Aung and colleagues conducted a genome-wide association study comprising 4,445 Singaporean subjects, with 2,132 of Indian ancestry and 2,313 of Malayan ancestry. An identical study included 9,326 Caucasian subjects from the Rotterdam Study conducted in the Netherlands.
Subjects in Singapore underwent measurement of optic disc area with Heidelberg Retina Tomography 2 (HRT2). Subjects in the Netherlands underwent imaging with the Topcon TRC-SS2 stereoscopic fundus camera (Topcon Optical) with ImageNet software.
Scans with a topographic standard deviation exceeding 50 m were excluded from analysis.
The Illumina Human610-Quad BeadChip was used to genetically analyze the Asian subjects. The Illumina Infinium II HumanHap550chip v3.0 array was used to identify genes in the Caucasian subjects.
All subjects underwent rigorous quality control checks.
Investigators identified a novel gene, Capase recruitment domain-containing protein 10, or CARD10, in Asian subjects; the gene was later confirmed to exist in the European cohort as well.
“CARD10 appears to have a strong effect in Asians and a substantially weaker but still very significant effect in Europeans,” Dr. Aung said.
Five single nucleotide polymorphisms from the CARD10 locus also showed a statistically significant association with optic disc area in the European cohort (P < .0005).
In addition, the scientists confirmed an association between the genes TGFBR3 and ATOH7 and optic disc area in the Asian subjects. The two genes were previously identified in European subjects.
“Genetic polymorphisms within ATOH7, TGFBR3 and CARD10 all affect optic disc size across Asians and Europeans,” Dr. Aung said.
Clinical implications
The results underscore the role of key anatomic features such as the optic disc in the glaucomatous cascade. CARD10 is believed to be involved in regulation of apoptosis, or cell death, which affects ganglion axonal cell survival, according to Dr. Aung and colleagues.
“[CARD10] is likely to be part of a longer molecular cascade,” Dr. Aung said. “CARD10 plays a critical role in the regulation of apoptosis, orchestrated cell death, and subtle mutations within it could conceivably cause differences in optic disc size due to differential survival of the nerve cells on the disc.”
Individual phenotypes underlying primary open-angle glaucoma should be studied to identify discrete genes involved in the disease, the authors said.
In addition, data showed no tangible associations between CARD10, ATOH7 and TGFBR3 and ocular structures apart from the optic disc.
“We looked at vertical cup-disc ratio and the neuroretinal rim. Any associations observed were abolished when the analysis was adjusted for optic disc size,” Dr. Aung said. – by Matt Hasson
Reference:
Khor CC, Ramdas WD, Vithana EN, et al. Genome-wide association studies in Asians confirm the involvement of ATOH7 and TGFBR3, and further identify CARD10 as a novel locus influencing optic disc area. Hum Mol Genet. 2011;20(9):1864-1872.
For more information:
Tin Aung, MBBS, N/MEd (Ophth), FRCS (Ed), FRCOphth, FAMS, PhD, can be reached at Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751; +65-63-228-313; fax: +65-62-263-395; email: tin11@pacific.net.sg.
Disclosure: Dr. Aung has no relevant financial disclosures.