A common, protein-coding variant of SIX6 is associated with reduced retinal nerve fiber layer thickness

Abstract

Purpose: Recently the common SIX6 missense variant, rs33912345, was found to be highly associated with glaucoma. The aim of this study was to investigate the association between this SIX6 variant with peripapillary retinal fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) in a population setting.

Methods: Study subjects were enrolled from the Singapore Chinese Eye Study (SCES), a population-based survey of Singaporean Chinese aged 40 years or older. Subjects underwent a comprehensive ocular examination. SD-OCT was used to measure RNFL thicknesses. Genotyping of SIX6 rs33912345 (Asn141His) was performed using HumanExome BeadChip (llumina Inc., CA).

Results: 2,129 eyes from 1,243 SCES subjects (mean age: 55.0±7.4 years) with rs33912345 genotype data and SD-OCT images were included in the analysis. Of these, 26 eyes of 21 subjects had glaucoma. The frequency of rs33912345 risk variant C (His141) was 80% in the study subjects. Each rs33912345 C allele was associated with a decrease of 1.44 μm in RNFL thickness, after adjusting for age, gender, genetic principal components, and axial length (P=0.001). These associations remained similar in 2,096 non-glaucoma eyes where each C allele was associated with a decrease of 1.39 μm in RNFL thickness (P=0.001). The strongest association was observed in the superior RNFL sector (a decrease of 2.83 μm per risk allele, P<0.001) followed by the inferior RNFL sector (a decrease of 2.24 μm per risk allele, P=0.003); while the association did not reach significance in the nasal and temporal sectors.

Conclusions: Non-glaucomatous individuals with the SIX6 missense variant have reduced RNFL thickness in regions known to be particularly affected in those with glaucoma. This reduced RNFL thickness implies a corresponding loss in the number of retinal ganglion cells (RGCs). Individuals carrying the risk allele may be born with fewer RGCs, or may lose RGCs at a greater rate throughout life. This may be the primary mechanism for increased risk of POAG in individuals who carry the SIX6 His141 risk variant.