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Jamie E Craig, Jude Fitzgerald, Soo Ng, Mona Awadalla, Alex W Hewitt, David A Mackey, Rhys Fogarty, Kathryn P Burdon; Epigenetic associations at the 9p21 glaucoma locus contribute to a female bias in normal tension glaucoma.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2147.
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We have recently shown that common SNPs at the 9p21 glaucoma locus (CDKN2B) are the strongest association signals for primary open angle glaucoma (POAG), and this locus is more strongly associated with normal tension glaucoma (NTG) and advanced glaucoma. We aimed to determine whether methylation in the CDKN2B promoter is associated with normal tension glaucoma, and to examine whether any observed differences in epigenetic associations are influenced by gender.
Gender was assessed as a risk factor for advanced POAG in 1275 cases from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) after excluding cases with pseudoexfoliation syndrome. NTG was defined as POAG in which the maximum recorded IOP was less than or equal to 21mmHg. In 202 cases with advanced NTG and 178 controls matched for age and gender, methylation status was determined at 28 CpG dinucleotides in the CDKN2B promoter region using the Epityper MassCleave assay on the Sequenom platform. Significant results were further investigated using pyrosequencing. All results were subanalysed by gender.
A significant gender bias was present within the ANZRAG NTG cases (55.9% female versus 44.1% male, p<0.004), whereas males were overrepresented in HTG cases, implying that recruitment bias is not an important factor. Methylation at 2 adjacent CpG dinucleotides in the CDKN2B promoter was significantly lower in NTG cases versus matched controls (4.6% vs 5.7%, p=0.001). The methylation difference in females (4.3% vs 5.6%, p=0.006, Mann-Whitney U test) was more marked in females than males. This result was confirmed with pyrosequencing in which methylation was significantly lower in female NTG cases (p=0.015) but not males (p=0.497).
We show for the first time that epigenetic effects at the 9p21 locus are associated with NTG. A disease registry approach has shown that female gender is a risk factor for development of advanced normal tension glaucoma. Epigenetic signals at the 9p21 locus appear to be stronger in females, raising the possibility that this mechanism could contribute to the observed gender bias for NTG.
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