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Abhishek Nag, Adriana I Iglesias, Pieter W.M. Bonnemaijer, Cornelia van Duijn, Caroline Klaver, Pirro G Hysi, Christopher J Hammond; Evaluation of the myocilin mutation Gln368Stop demonstrates reduced penetrance for glaucoma in European populations. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1229. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Sequence variations in the myocilin (MYOC) gene account for ~2–4% of the glaucoma cases. One particular MYOC mutation, Gln368Stop (dbSNP accession number: rs74315329), is the commonest genetic mutation causing primary open-angle glaucoma (POAG), by raising the intraocular pressure (IOP). Previous studies have reported that this mutation has a penetrance as high as 90-100% with respect to ocular hypertension or POAG. The objective of our study was to evaluate the penetrance of the Gln368Stop MYOC mutation i.e. the risk allele of rs74315329 on IOP (as a proxy for POAG) using data from large-scale European population panels (directly sequenced and imputation-based).
In the TwinsUK study (N=6,092; mean age = 57 years), carriers of the risk allele of rs74315329 were identified using sequencing data, while the same in the Rotterdam study (N=11,189; mean age = 64 years) were identified using imputed data based on the Haplotype Reference Consortium panel. The penetrance of the risk allele of rs74315329 was estimated using IOP measurements (high IOP or ocular hypertension was defined as mean IOP > 21 mm Hg), history of IOP-lowering medication and / or visual field testing information / a diagnosis of glaucoma.
In the TwinsUK, one out of the eight risk allele carriers for rs74315329 had high IOP and a diagnosis of glaucoma. In the Rotterdam study, 6 out of the 31 risk allele carriers for rs74315329 had high IOP or a history of IOP-lowering medication (two of the six risk allele carriers had a diagnosis of glaucoma). For rs74315329, this corresponds to a penetrance of 12.5% and 19.4% in relation to ocular hypertension, in the TwinsUK and the Rotterdam study, respectively. This suggests a much lower penetrance for rs74315329 for ocular hypertension (and hence, POAG) observed in our study, in comparison to that reported previously.
We report findings of the largest study to date evaluating the penetrance of the Gln368Stop MYOC mutation i.e. rs74315329 using large-scale population-based sequencing panels, which we believe might represent a more “realistic” measure of its penetrance compared to previous estimates. The significance of this finding is that higher numbers of healthy individuals in the population are expected to be carriers of this mutation, which in turn reduces the utility of identifying carriers of this mutation as a screening tool for glaucoma.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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