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A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population

The EPIC-Norfolk Eye Study

Khawaja, Anthony P. PhD, FRCOphth*,†; Chan, Michelle P.Y. PhD, FRCOphth; Yip, Jennifer L.Y. PhD; Broadway, David C. MD, FRCOphth§; Garway-Heath, David F. MD, FRCOphth*; Viswanathan, Ananth C. PhD, FRCOphth*; Luben, Robert BSc; Hayat, Shabina MSc; Hauser, Michael A. PhD∥,¶; Wareham, Nicholas J. PhD#; Khaw, Kay-Tee MA, MBBChir; Fortune, Brad PhD**; Allingham, R. Rand MD; Foster, Paul J. PhD, FRCOphth*,‡

doi: 10.1097/IJG.0000000000001026
Original Studies

Purpose: A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population.

Methods: We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length, and intraocular pressure. We further repeated analyses stratified into age tertiles.

Results: In total, 5433 participants with HRT data and 3699 participants with GDxVCC data were included. Each “C” allele of rs33912345 was associated with a smaller rim area (−0.030 mm2 [95% CI −0.040, −0.020]; P=5.4×10−9), a larger VCDR (0.025 [95% CI 0.017, 0.033]; P=3.3×10−10) and a thinner RNFL (−0.39 μm [95% CI -0.62, -0.15]; P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles.

Conclusions: The protein-coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans.

*NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology

Division of Genetics and Epidemiology, UCL Institute of Ophthalmology, London

Department of Public Health & Primary Care, University of Cambridge

#MRC Epidemiology Unit, Addenbrookes Hospital, Cambridge

§Department of Ophthalmology, Norfolk and & Norwich University Hospital, Norwich, UK

Department of Ophthalmology, Duke University Medical Center

Department of Medicine, Duke University Medical Center, Durham, NC

**Devers Eye Institute and Legacy Research Institute, Portland, OR

R.R.A. and P.J.F. contributed equally.

EPIC-Norfolk infrastructure and core functions are supported by grants from the Medical Research Council (G1000143) and Cancer Research UK (C864/A14136). The clinic for the third health examination was funded by Research into Ageing (262). Genotyping was funded by the Medical Research Council (MC_PC_13048). A.P.K. is supported by a Moorfields Eye Charity grant. M.P.Y.C. is a joint Medical Research Council/Royal College of Ophthalmologists Research Fellow and received additional support from the International Glaucoma Association. P.J.F. has received additional support from the Richard Desmond Charitable Trust (via Fight for Sight) and the Department for Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital and the UCL Institute of Ophthalmology for a specialist Biomedical Research Centre for Ophthalmology.

Disclosure: The authors declare no conflict of interest.

Reprints: Anthony P. Khawaja, PhD FRCOphth, NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, 11-43 Bath St, London EC1V 9EL, UK (e-mail:

Received February 24, 2018

Accepted July 7, 2018

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