Ethnicity and the Genetics of Glaucoma

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By the time you realize that you’re a victim of the “silent thief of sight,” it may be too late. Vision loss due to glaucoma is permanent. Glaucoma, the second leading cause of blindness in the world, is a disease generally characterized by fluid buildup in the eye that increases intraocular pressure (IOP). Over time, the increased pressure damages the optic nerve (image) and leads to the loss of retinal ganglion cells, which transmit visual information from the eye to the brain. This causes progressive loss of peripheral vision and eventual blindness if left untreated (click for glaucoma simulator). Because vision loss is slow, it’s easy for patients not to realize that they are losing their sight until they are bumping into tables and tripping over misplaced shoes.

Eye disease simulation, normal vision

Normal range of vision

Eye disease simulation, glaucoma

A scene as it might be viewed by a person with glaucoma.

Glaucoma isn’t exactly an equal opportunity thief, either. While it is estimated that over 4 million Americans have glaucoma, the prevalence of glaucoma in African Americans and Latino (particularly Mexican) Americans is significantly greater than in Caucasian Americans. African Americans are also more likely to develop glaucoma at a younger age and suffer blindness from the disease. While roughly 90% of all glaucoma cases in the US are what is known as primary open angle glaucoma (POAG), Asian Americans are at the greatest risk of all ethnicities to develop a different form of glaucoma called primary angle closure glaucoma (PACG)(1). The genetic causes underlying glaucoma remain unclear, but these ethnic disparities in the risk of developing glaucoma suggest a genetic basis that is ethnicity-specific.

Recently, scientists have undertaken large scale genetic studies to identify mutations in genes that might contribute to the causes of glaucoma. Identifying these mutations may help in the diagnosis, prevention, and perhaps treatment of glaucoma. These studies, known as genome-wide association studies (GWAS), exploit the fact that DNA sequences between human genomes vary. These sequence variations, called single nucleotide polymorphisms (SNP), occur throughout the genome, including within genes. In many ways SNPs can be thought of as different “spellings” of a gene.

In a GWAS, scientists compare the DNA sequences of two groups of people: one group with a particular trait or condition (in this case glaucoma) and another group without that trait or condition. When a particular SNP keeps popping up within the group that has the condition, then scientists flag that SNP (and the associated gene) as being associated with the condition. This would be similar to comparing books from the UK and the US and noting that the particular spelling of “behaviour” correlates with books from the UK. In some cases, these correlations can give us insight into the causes of a condition.

GWASs have been conducted in the past to identify SNPs that correlate with glaucoma. However, these studies, like two GWASs recently published in PLOS Genetics, have tended to focus mainly on PACG in Caucasian populations (2 & 3). Last year, the results from an exhaustive GWAS were published in Nature Genetics–significant, because rather than POAG, it focused on PACG in Asian populations (4). They report 3 SNPs that correlate with PACG. The first is found in the PLEKHA7 gene, which encodes the protein “pleckstrin homology domain–containing protein 7.” This protein has been implicated in maintaining structures, known as adherens junctions, that help connect cells to each other. In the eye, adherens junctions may help keep cells “sealed” together to prevent fluid leakage. This SNP may affect PLEKHA7’s ability to form a tight seal allowing the fluid buildup in the eye that raises IOP in glaucoma.

The second SNP was found in the gene COL11A1, which encodes one of the α chains of type XI collagen. Mutations in this gene have been associated with diseases that are characterized by hyperopia (farsightedness). Instead of hyperopia, however, the authors speculate that this particular variant might predispose an individual to myopia (nearsightedness), which is a known risk factor for glaucoma. The last SNP that correlated with PACG was located in DNA between two genes, PCMTD1 and ST18. It is unclear how this SNP might affect either genes (e.g. gene expression) and to date no potential connections with glaucoma have been determined for either gene.

It is important to note again that these studies reveal only correlation. The gene variants that these studies turn up may or may not contribute to the onset of glaucoma. For one, either through evolutionary selection or chance, a gene variant and a trait can become correlated in a population without the gene being the cause for that trait. For instance, consider the correlation between red hair and fair complexion. The gene variant for red, which is found most often in northern or western European ancestry, isn’t responsible for their fair complexion. Secondly, not all of these gene variants represent mutations that affect the function of the gene. This is because genes can tolerate some degree of sequence variation without major consequences. Again, thinking about genes as words and SNPs as spelling, we know that “behaviour” and “behavior” mean the same thing despite different spellings. “Two” and “too,” however, are entirely different words and replacing one with the other would dramatically alter the meaning of a sentence. One of the challenges that scientists face upon identifying a SNP by GWAS is determining if that SNP is simply an alternative spelling or a “typo” that carries with it consequences that impact health.

Currently, there is no cure for glaucoma. While a study from last year reported that human stem cells were able to partially restore vision in rats with damaged retinal ganglion cells, stem cell treatment for glaucoma in humans is still a long ways off. Therefore, prevention remains the best strategy against glaucoma. Even though IOP or ocular hypertension is one of the most dependable risk indicators for glaucoma, measuring eye pressure alone is often not enough. The NIH recommends dilated eye exams where “drops are placed in the eyes to dilate, or widen, the pupils. This allows an eye care professional to examine the optic nerve for signs of damage and other possible problems.”

Unfortunately, the ethnic disparities do not end with the risk of developing glaucoma. A recent report indicates that Hispanic Americans are least likely of any ethnic group to “get routine follow-up testing to make sure their vision wasn’t getting worse.” While I am unaware of any large scale GWASs conducted on populations of African or Latino descent, the rates of glaucoma are expected to increase dramatically for African and Latino/Hispanic Americans. Coupled with a fast growing Asian American population improving screening and diagnosis of glaucoma in minority groups will be critical in safeguarding their vision from being stolen.

*January is Glaucoma Awareness Month.*


1. Stein JD, Kim DS, Niziol LM, Talwar N, Nan B, Musch DC, Richards JE. Differences in rates of glaucoma among Asian Americans and other racial groups, and among various Asian ethnic groups. Ophthalmology. 2011 Jun;118(6):1031-7. doi:10.1016/j.ophtha.2010.10.024.

2. van Koolwijk LME, Ramdas WD, Ikram MK, Jansonius NM, Pasutto F, et al. (2012) Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma. PLoS Genet 8(5): e1002611. doi:10.1371/journal.pgen.1002611

3. Wiggs JL, Yaspan BL, Hauser MA, Kang JH, Allingham RR, et al. (2012) Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma. PLoS Genet 8(4): e1002654. doi:10.1371/journal.pgen.1002654

4. Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, Do T, Abu-Amero K, Huang CK, Low S, Tajudin LS, Perera SA, Cheng CY, Xu L, Jia H, Ho CL, Sim KS, Wu RY, Tham CC, Chew PT, Su DH, Oen FT, Sarangapani S, Soumittra N, Osman EA, Wong HT, Tang G, Fan S, Meng H, Huong DT, Wang H, Feng B, Baskaran M, Shantha B, Ramprasad VL, Kumaramanickavel G, Iyengar SK, How AC, Lee KY, Sivakumaran TA, Yong VH, Ting SM, Li Y, Wang YX, Tay WT, Sim X, Lavanya R, Cornes BK, Zheng YF, Wong TT, Loon SC, Yong VK, Waseem N, Yaakub A, Chia KS, Allingham RR, Hauser MA, Lam DS, Hibberd ML, Bhattacharya SS, Zhang M, Teo YY, Tan DT, Jonas JB, Tai ES, Saw SM, Hon do N, Al-Obeidan SA, Liu J, Chau TN, Simmons CP, Bei JX, Zeng YX, Foster PJ, Vijaya L, Wong TY, Pang CP, Wang N, Aung T. Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma. Nat Genet. 2012 Oct;44(10):1142-6. doi:10.1038/ng.2390

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