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Editors Selection IGR 16-2
Basic Science: A susceptibility gene in zebrafish and men
Comment by Calvin Pang on:
57288 Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma, Carnes MU; Liu YP; Allingham RR et al., PLoS Genetics, 2014; 10: e1004372
This is a paper on an important study that involves sequence characterization, functional analysis in zebrafish, and clinical investigation of patients carrying specific sequence variants. First, the identification of a common variant, Asn141His (rs33912345), in the SIX6 gene and its association with primary open-angle glaucoma (POAG, p = 4.2 x 10-10) was reported. In another study by Iglesias et al.,1 rs33912345 was also associated with POAG (p = 6.09 x 10-3). This variant is in linkage disequilibrium with another SIX6 variant rs10483727, which was associated with POAG in a genome-wide association study by Wiggs et al.2 These findings together give evidence for SIX6 as a susceptibility gene of POAG.
Carnes et al. Also demonstrated that the SIX6 variants have functional impacts on SIX6 expression and protein function. Particularly, an approximately threefold reduction in optic nerve volume was found upon depletion of the six6a ortholog in Zebrafish, indicating the involvement of SIX6 in the development of the optic nerve. SIX6 thus may have biological implications in glaucoma.
In clinical investigations of 30 POAG patients, Carnes et al. Found that the rs33912345 risk allele (C) was correlated with thinner retinal nerve fiber layers (RNFL). Interpretation of this, however, should be cautious, as the authors did not address the severities of glaucoma in the patients. It is possible that patients carrying the C allele might have more advanced glaucoma than those with the non-risk allele (A). Glaucoma staging and severity should be taken into account. Nevertheless, in a recent study by Cheng et al.,4 the C allele was associated with thinner RNFL in nonglaucomatous eyes, in line with the findings of this paper, which gives important information on the association of SIX6 variants with the progression of RNFL loss in glaucoma.
References
- Iglesias AI, Springelkamp H, van der Linde H, et al. Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferationdifferentiation balance early in life and optic nerve degeneration at old age. Hum Mol Genet. 2014;23:1320-1332.
- Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet. 2012;8(4):e1002654.
- Cheng CY, Allingham RR, Aung T, et al. Association of Common SIX6 Polymorphisms With Peripapillary Retinal Nerve Fiber Layer Thickness: The Singapore Chinese Eye Study. Invest Ophthalmol Vis Sci. 2014;56:478-483.
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