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Shane J Havens, Joanne C Wen, Megan Ulmer Carnes, Janey L Wiggs, Louis R Pasquale, Allison E Ashley-Koch, Michael A Hauser, R Rand Allingham, NEIGHBORHOOD Consortium Investigators; The retinal nerve fiber layer is reduced in POAG cases homozygous for the common Six6 risk-allele of rs33912345 (Asn141His). Invest. Ophthalmol. Vis. Sci. 2014;55(13):3799.
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Single nucleotide polymorphisms (SNPs) in the SIX6 gene have been associated with POAG. A common coding variant of SIX6, rs33912345 (Asn141His), has been shown to have an effect on eye size in the zebra fish model. In this study we compared the structural optic nerve features among POAG subjects homozygous for the risk allele (141His) to those with the non-risk allele (141Asn).
Subjects from the Duke POAG case-control dataset were included in the NEIGHBOR genome-wide association study. Genotypes for the SNP rs33912345 were imputed and individuals homozygous for the risk and non-risk alleles were identified. Clinical data from each subject, including age at POAG diagnosis, central corneal thickness (CCT), refractive error, and retinal nerve fiber (RNFL) thickness measured by spectral domain ocular coherence tomography (OCT) (Spectralis®, Heidelberg Engineering, Germany) were compared using a student t-test.
There were 23 POAG cases homozygous for the risk allele and 42 with the non-risk allele. There was no significant difference in age at POAG diagnosis (p=0.11) or at time of OCT testing (p=0.14) between the risk and non-risk groups. There was no significant difference in spherical equivalent or astigmatic error. POAG cases homozygous for the risk allele had thinner RNFL across all quadrants (global thickness; risk allele=58.1 +/- 9.9 μm, non-risk=68.3 +/- 19, p=0.03). A significant reduction in thickness was observed in the superior (risk=63.8 +/- 19 μm, non-risk=79.7 +/- 28, p=0.04) and inferior (risk=65.3 +/- 22.1 μm, non-risk=80.9 +/- 28, p=0.03) quadrant RNFL measurements in POAG cases homozygous for the risk allele.
RNFL measured by sd-OCT is thinner in POAG cases homozygous for the Asn141His SIX6 risk allele compared to POAG cases with the non-risk allele. The difference in RNFL was observed for global thickness measurement as well as the superior and inferior quadrants. These data support the finding in the zebra fish model that the Asn141His allele of SIX6 may be functional in POAG cases. The SIX6 risk allele may reduce the number of retinal ganglion cells formed during development or increase susceptibility to ganglion cell death, or both. If these findings are confirmed, this is the first genetic association of a common variant identified by genome-wide association studies that has a functional disease-related effect in POAG.
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