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Editors Selection IGR 9-2

Basic Research: MYOC is still alive as an OAG gene

Comment by Julie Richards on:

26174 Little evidence for association of the glaucoma gene MYOC with open-angle glaucoma, Sohn S; Hur W; Choi YR et al., British Journal of Ophthalmology, 2010; 94: 639-642

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Sohn et al. (613) used three different approaches to investigate the role of myocilin (MYOC) in open-angle glaucoma (OAG). Firstly, they used cultured cells to show that "[..] eye drops with a low IOPelevating potential induced MYOC to the same extent as eye drops with a high IOP-elevating potential." They concluded that elevated MYOC does not cause IOP elevation in vivo in steroid-induced glaucoma. However, differences in processing or transport of two different drugs through organ cell layers can lead to differences in effective dose in vivo that do not happen in vitro. Even if this were observed in vivo, it could be explained by a multi-factorial model involving a threshold effect for MYOC. Thus a conservative interpretation of the data does not exclude MYOC effects on IOP. Secondly, they show that MYOC is not induced in cultured cells exposed to static elevation of pressure. They conclude that "MYOC overexpression is not a cause or an effect of intraocular pressure elevation." However, they did not investigate two other important pressure mechanisms, shear stress and stretch. Their results stand in contrast to MYOC induction of elevated IOP in a human organ culture model (Borrás et al. IOVS 2002; 43: 33-40). Finally, Sohn et al tested for association of MYOC promoter sequence variants with presence of three different forms of OAG. They did no statistical test for association and their three case cohorts were small. They conclude, "We also showed that the MYOC gene itself is not associated with OAG," and say that this "was somewhat unexpected, because MYOC had been considered to be a susceptibility gene for POAG." But association of OAG with several promoter variants had previously been excluded (Alward et al. Arch Ophthalmol 2002; 120: 1189-1197); linkage and association test for different things so this did not contradict the strong evidence for MYOC as a glaucoma gene that has come from many family-based linkage studies involving a highly heterogeneous group of coding sequence mutations (Stone et al. 1997; 275: 668-670). Sohn and colleagues have shown 1) a lack of correspondence between in-vitro MYOC induction in response to certain drug doses and in-vivo IOP responses to those same drug doses; 2) a lack of MYOC induction in vitro in response to static pressure; and 3) a possible lack of association of multiple MYOC promoter sequence variants with three different glaucoma phenotypes. While these findings are interesting, there is nothing in the paper to back their broad assertion that "MYOC itself is not associated with OAG."

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