SIX6 gene linked to higher glaucoma risk due to thinner RNFL

The SIX6 genetic locus plays a role in the thinning of the retinal nerve fibre layer (RNFL) in otherwise healthy eyes, reports a recent Singapore study.

“Our findings provided a more comprehensive insight into the complex genetic architecture underlying glaucoma and the role of SIX6 in determining RNFL thinning,” researchers said. “This suggests that subjects with the SIX6 genetic risk variant are at higher risk for glaucoma due to thinner RNFL.”

In 3,843 participants (7,020 eyes; mean age, 59.4±8.9 years; 50.2 percent female), the average RNFL thickness was 92.3±11.2 µm. The study cohort was ethnically diverse: 1,303 were Chinese, 1,433 were Indian, and 1,107 were Malay. The ethnic subgroups, however, were different from each other in terms of baseline characteristics. [Invest Ophthalmol Vis Sci 2020;61:37]

Notably, global RNFL was lowest in the Indian participants than in both Chinese and Malay comparators, and the difference among groups was statistically significant (p<0.001).

In single-cohort analysis, the rs33912345 single nucleotide polymorphism (SNP) in the SIX6 locus was found to be significantly associated with thinner superior RNFL thickness in Chinese participants (β, –2.479; p=0.001). No such effect was reported for global and inferior RNFL thickness in any of the ethnic subgroups.

A meta-analysis of all three ethnic groups further validated these findings. Of the 35 loci investigated, only SIX6 emerged as a significant correlate of thinner global (p=1.64×10^–5), superior (p=6.5×10^–5), and inferior (p=2.9×10^–6) RNFL. Other loci, including the CDKN1A, CDKN2B-AS1, and 8q22, among others, were of nominal significance (p<0.05).

In addition, SIX6 was significantly associated with rim area (β, –0.052; p=1×10^–8) and disc area (β, –0.055; p=3.42×10^–8), but not with vertical cup-to-disc ratio (p=0.006).  Additional adjusting for these factors did not attenuate the interaction between SIX6 and RNFL thickness in the overall cohort meta-analysis.

“[T]his is the first study comparing effect of glaucoma risk genes on RNFL across multiple ethnic groups in Asians,” the researchers said. “These findings may provide further insights into the genetic variants associated with pathogenesis of glaucoma.”

In the present analysis, participants were enrolled from the Singapore Epidemiology of Eye Disease study and underwent spectral-domain optical coherence tomography imaging. Samples for genotyping were subject to strict and routine quality controls to remove those that were producing data of poor quality. A literature review was conducted to determine the panel of glaucoma risk loci to be investigated in the current study.

The findings of the present study suggest “that glaucoma risk genes may have different effects on RNFL thinning and disc alteration, and RNFL thinning in glaucoma is most likely a manifestation of various ocular insults rather than a direct effect of the gene products and their associated pathway on the integrity of RNFL,” the researchers said.

“Further studies are needed to evaluate the mechanisms in which these genes predispose individuals to glaucoma,” they added.