Genetic variants linked with onset, progression of POAG

April 23, 2020

Genetic variants that are unrelated to the IOP are associated with a family history of glaucoma and play a role in the onset of primary open-angle glaucoma (POAG). Genetic variants that are related to the IOP are associated with the age at which glaucoma is diagnosed and are associated with disease progression.

What is known about POAG, the most prevalent form of glaucoma, is that increased IOP and myopia are risk factors for damage to the optic nerve in POAG. 

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A family history of glaucoma is a major risk factor for development of POAG, in light of which, therefore, genetic factors are thought to be important in the disease pathogenesis and a few genes mutations have been identified as causing POAG, according to Fumihiko Mabuchi, MD, PhD, professor, Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Kofu, Japan.

Myopia has been shown to be a risk factor for POAG in several studies. However, it can be difficult to diagnose true POAG in myopic patients and controversy exists over whether it is real risk factor. 

Myopic optic discs are notoriously difficult to assess, and myopic patients may have visual field defects unrelated to any glaucomatous process. 

The prevalence of POAG increases with age, even after compensating for the association between age and IOP.

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Part of the story
Dr. Mabuchi and his and colleagues, recounted that these factors are only part of the story.

According to Dr. Mabuchi and his colleagues, “…cases of POAG caused by these gene mutations account for several percent of all POAG cases, and most POAG is presumed to be a polygenic disease.” 

Recent genetic analyses, the investigators explained, have reported genetic variants that predispose patients to development of POAG and the additive effect of these variants on POAG, which are classified as two types. 

The first genetics variants are associated with IOP elevation. 

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The second genetic variants are genetic variants that are not related to the IOP but are associated with optic nerve vulnerability, including apoptosis of the optic nerve, myopia, and optic nerve circulation. 

In their previous work, the investigators reported the additive effects of these two types of genetic variants (Am J Ophthalmol 2015;159:437-444 e432; and Plos One 2017;12:e0183709) on the IOP and POAG, including normal-tension and high-tension glaucomas (NTG and HTG, respectively).

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Genetic study
In this case -controlled genetic association study, they took their research a step further in their efforts to clarify the genetic mechanism of the onset and progression of POAG by investigating “the association between the IOP-/non-IOP-related genetic variants and family history of glaucoma as an indicator of the onset of POAG and age at the diagnosis of glaucoma as an indicator of the progression of POAG.” 

The investigators reported their findings in the American Journal of Ophthalmology (2020, doi: https://doi.org/10.1016/j.ajo.2020.03.014).

The patients were recruited from three hospitals and one clinic in Japan. 

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A total of 505 Japanese patients with POAG (including 246 with HTG and 259 with NTG) and 246 control subjects (mean patient age, 63.7 years; mean control subject age, 67.7 years) were included in the study. 

According to the researchers, the mean maximal IOP levels in the patients and control subjects, respectively, were 23.3 mmHg and 15.0 mmHg. In the patients with glaucoma, the mean age at POAG diagnosis and the prevalence of a family history of glaucoma were 56.8 years and 25.5%. 

All participants underwent genotyping for 22 genetic variants that predispose to POAG that could be classified into those variants associated with IOP elevation (17 genetic variants) or optic nerve vulnerability independent of the IOP (five genetic variants), Dr. Mabuchi and colleagues explained.

IOP remains the main risk factor for glaucoma assess and progression. The genetic risk score (GRS) of POAG was calculated, which was comprised of the total number of risk alleles of the 17 IOP-related genetic variants and the five non-IOP-related genetic variants.

The investigators then evaluated the associations found between the GRS and the family history of glaucoma, as an indicator of POAG onset, and age at glaucoma diagnosis, as an indicator of POAG progression.

Several genes associated with POAG have been identified, though these account for less than 5% of all POAG in the general population.

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Results
The study identified two noteworthy findings. 

The results showed a significant (P=0.014, odds ratio [OR], 1.26 per GRS) association between the non-IOP-related GRS and a family history of glaucoma. “As the non-IOP-related GRS increased, the risk of a family history of glaucoma increased in patients with POAG,” the investigators reported.

Regarding the association between the GRS and the age at which glaucoma was diagnosed, the investigators reported a significant (p = 0.0014, beta, -0.14) association between the IOP-related GRS and the age at diagnosis of glaucoma. “As the IOP-related GRS increased, the age at the diagnosis of glaucoma decreased,” they stated. 

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“In summary, a family history of glaucoma in cases of POAG is thought to reflect the influence of genetic variants predisposing to POAG, especially non-IOP-related genetic variants, and therefore accounts for the role of a positive family history of glaucoma as a risk factor for POAG. In contrast, IOP-related rather than non-IOP-related genetic variants were associated with age at the diagnosis of glaucoma, Dr. Mabuchi and colleagues commented.

“These results indicate that optic nerve vulnerability to IOP due to non-IOP-related genetic variants plays an important role in the onset of POAG. IOP elevation induced by IOP-related genetic variants plays an important role in the progression of POAG,” Dr. Mabuchi concluded. “The present findings are useful for understanding the pathogenesis of POAG.” 

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