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Mei Chin Lee, Anita Chan, Yaan Fun Chong, Eranga Nishanthie Vithana, Chiea Chuen Khor, Tin Aung; Rare, non-synonymous variants at CACNA1A have a limited role in the pathogenesis for exfoliation syndrome.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5146. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Exfoliation syndrome (XFS) is the commonest cause of secondary glaucoma world-wide. Large-scale genetic association studies have revealed significant associations at 7 common-variant loci. Despite this, the genetic architecture underlying XFS remains poorly understood. Here, we hypothesize that rarer mutations of higher penetrance present within the previously reported GWAS locus of CACNA1A may explain the common variant signal marked by sentinel SNP rs4926244 (Aung T et al., 2015, 2017).
Targeted re-sequencing were conducted on CACNA1A locus in 5,566 XFS cases and 6,279 controls. Average depth of coverage at 88X per-sample, with equal sequencing depth between XFS cases and controls were achieved. Association analysis was performed via a collapsing burden test whereby rare genetic variants within the CACNA1A coding frame was collapsed into a single allele (Do R et al., Nature 2014). Frozen and paraffin-embedded human globes were sectioned and used for immunofluorescence analysis of CACNA1A expression via immunofluorescence analysis on 5 XFS cases and 4 non-XFS controls.
Previous studies revealed (Aung T, Ozaki M, Lee MC et al., 2017), rare non-synonymous variants do not collectively associate with XFS disease risk. However, when examined for frame-shift mutations and in-frame amino acid insertions and deletions, more than two-fold enrichment of such mutations (P<0.05) in XFS cases (overall frequency of 3.5%) compared to controls (overall frequency of 1.6%) were observed. 4 frame-shift mutations were observed in XFS cases, but only 1 in age-matched controls (OR = 4.27, P = 0.16), leading to a non-significant trend towards increased risk of disease in terms of frame-shift mutations.Although the genetic data suggest a possible role for disruptive mutations that may reduce expression of CACNA1A, our immunofluorescence microscopy data showed no significant differences in CACNA1A expression within the ciliary body and iris tissues from both XFS cases and non-XFS controls.
Our data shows that non-synonymous, rarer mutations at CACNA1A do not appear to be responsible for the associations seen with common, non-coding GWAS variants in the context of XFS. However, there is a potential role for disruptive frame-shift variants and amino acid insertions and deletions. Further work will be needed to verify this observation.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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