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Editors Selection IGR 22-1

Basic Science: Gene studies in POAG, NTG and exfoliation glaucoma

Comment by Louis Pasquale on:

51021 Association of Toll-like receptor 4 gene polymorphisms in Japanese subjects with primary open-angle, normal-tension, and exfoliation glaucoma, Takano Y; Shi D; Shimizu A et al., American Journal of Ophthalmology, 2012; 154: 825-832.e1

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Takano et al. Assess whether eight Toll-like receptor 4 (TLR4) single nucleotide polymorphisms (SNPs) are associated with three types of glaucoma ‐ primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG) and exfoliation glaucoma (EG). The variants chosen span TLR4 and were meant to serve as a replication for a prior study indicating TLR4 SNPs were associated with NTG in a Japanese population, even after correcting for multiple comparisons.¹ TLR4 on macrophages serves as the gateway for activating the innate immune system in response to microbial antigens. TLR4 activation triggers tumor necrosis alpha (TNFα) production, which is implicated in mediating retinal ganglion cell death in glaucoma.² It is possible that TLR4 SNPs alter TNFα production and contribute to glaucoma, particularly the normal-tension variant. In fact, the authors included 365 NTG patients (versus the 250 NTG patients the initial study)¹ compared to 206 controls as they were particularly interested in relation between TLR4 SNPs and NTG. Post-hoc correction for multiple comparisons with the conservative Bonferroni test indicates that they were not able to replicate the prior association between TLR4 SNPs with NTG, despite the larger sample size. Furthermore, the association with EG was also weak and could represent false positive discovery. Takano et al. did find a strong association between an intron 2 TLR4 variant and POAG using 184 cases that stands up to conservative approaches to correct for multiple comparisons but this result requires replication in another population. The toll receptors collectively are a 13-member family that represents the 'eyes of the innate immunity system'³ and stimulation of any one of them could lead to neuro-inflammation. Thus a comprehensive and adequately powered gene association study between toll-like receptor family polymorphisms and open-angle glaucoma is indicated.

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