Association of Polymorphisms at the<i>SIX1-SIX6</i>Locus With Primary Open-Angle Glaucoma

Lu, Shijuan; He, Zong Ze; Xu, Jia; Yang, Chen; Chen, Li Jia; Gong, Bo

doi:10.1167/iovs.18-26489

Cited by 15 publications

(22 citation statements)

References 57 publications

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“…However, in the case of POAG and SIX1/SIX6 , it is not known when these genetic variants start exerting their effects 24 . Studies have reported that individuals with risk allele in SIX1/SIX6 are more susceptible to glaucoma 1 , 3 , 25 and have thinner RNFL 20 – 23 . Note that these RNFL studies were conducted in older individuals, hence it is not clear whether thinner RNFL found in the older individuals with SIX1/SIX6 variants is due to these individuals being born with thinner RNFLs or due to a faster rate of RNFL degeneration as they age.…”

Section: Discussionmentioning

confidence: 99%

Age-dependent regional retinal nerve fibre changes in SIX1/SIX6 polymorphism

Charng

Simcoe

Sanfilippo

et al. 2020

Sci Rep

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SIX1/SIX6 polymorphism has been shown to be associated with glaucoma. Studies have also found that, in older adults, retinal nerve fibre layer (RNFL) thickness is significantly thinned with each copy of the risk allele in SIX1/SIX6. However, it is not known whether these genetic variants exert their effects in younger individuals. Comparing a healthy young adult with an older adult cohort (mean age 20 vs 63 years), both of Northern European descent, we found that there was no significant RNFL thinning in each copy of the risk alleles in SIX1/SIX6 in the eyes of younger individuals. The older cohort showed an unexpectedly thicker RNFL in the nasal sector with each copy of the risk allele for both the SIX1 (rs10483727) and SIX6 (rs33912345) variants. In the temporal sector, thinner RNFL was found with each copy of the risk allele in rs33912345 with a decrease trend observed in rs10483727. Our results suggest that SIX1/SIX6 gene variants exert their influence later in adult life. Genome-wide association (GWA) studies have identified multiple genetic variants that increase susceptibility to Primary Open-Angle Glaucoma (POAG) 1-3. Among these, the rs10483727 variant in the SIX1 region was significantly associated with POAG diagnosis and progression in a quantitative trait GWA study 4 and with risk of POAG in a later case-control GWA study 3. More importantly, the rs10483727 variant was associated with POAG across different ethnicities 2,5-8. However, to date, no causal variants driving its association with POAG have been identified. Similarly, the effect of rs10483727 on protein function remains unknown. The missense variant rs33912345 (Asn141His), found in the SIX6 locus 9 , is in strong linkage disequilibrium with rs10483727. It is also associated with POAG and has been shown to alter the function of the SIX6 protein 10. SIX6 is involved in the differentiation and survival of retinal ganglion cells 11,12 , which are the primary cells affected in POAG. Both SIX1 and SIX6 belong to the family of sine oculis (SIX) transcription factors with six members in mammals (SIX1 to SIX6). All members of the family are characterized by the presence of two highly conserved domains: a homeobox domain and a SIX domain 13,14. SIX1 is expressed in several tissues, including the optic vesicles and the limb mesenchyme, but it is poorly expressed in the eye. In contrast, studies in different species, including humans, have shown that SIX6 is highly expressed in the developing retina, especially in the retinal ganglion and the amacrine cells 11,15,16. Genetic inactivation of SIX6 has been shown to result in hypoplasia of the mice retina, which subsequently lead to absence of the optic nerves 16. It is well established that POAG results in thinning of the retinal nerve fibre layer (RNFL) 17,18 , thus RNFL assessment has become indispensable in POAG management 19. Polymorphisms in SIX6 and SIX1 have been reported to result in significant RNFL thinning but the region of RNFL thinning has varied depending on the study. More specifically, each...

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Section: Discussionmentioning

confidence: 99%

Age-dependent regional retinal nerve fibre changes in SIX1/SIX6 polymorphism

Charng

Simcoe

Sanfilippo

et al. 2020

Sci Rep

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“…Moreover, mutations in paired box 6 (PAX6) gene are rare with large biological effect and are closely associated with the pathogenesis of developmental glaucoma related to anterior segment dysgenesis [91]. Variants of genes with common frequency and low effect size leading to the development of POAG include the following: Cyclin-dependent kinase inhibitor 2B (CDKN2BAS), caveolin 1 and caveolin 2 (CAV1/CAV2), sine oculis homeobox homolog 1 and sine oculis homeobox homolog 6 (SIX1/SIX6), transmembrane and coiled-coil domains 1 (TMCO1), growth arrest specific 7 (GAS7), atonal homolog 7 (ATOH7), and RPGR Interacting Protein 1 (RPGRIP1) [88,91,[99][100][101][102][103][104][105][106][107].…”

Section: Genes As Risk Factors For Poag Pathogenesismentioning

confidence: 99%

The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

Rozpędek‐Kamińska

Wojtczak

Szaflik

et al. 2020

IJMS

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Glaucoma is a heterogenous, chronic, progressive group of eye diseases, which results in irreversible loss of vision. There are several types of glaucoma, whereas the primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma, accounting for three-quarters of all glaucoma cases. The pathological mechanisms leading to POAG pathogenesis are multifactorial and still poorly understood, but it is commonly known that significantly elevated intraocular pressure (IOP) plays a crucial role in POAG pathogenesis. Besides, genetic predisposition and aggregation of abrogated proteins within the endoplasmic reticulum (ER) lumen and subsequent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent unfolded protein response (UPR) signaling pathway may also constitute important factors for POAG pathogenesis at the molecular level. Glaucoma is commonly known as a ‘silent thief of sight’, as it remains asymptomatic until later stages, and thus its diagnosis is frequently delayed. Thereby, detailed knowledge about the glaucoma pathophysiology is necessary to develop both biochemical and genetic tests to improve its early diagnosis as well as develop a novel, ground-breaking treatment strategy, as currently used medical therapies against glaucoma are limited and may evoke numerous adverse side-effects in patients.

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“…During embryonic development, SIX1 is expressed broadly in multiple tissues, including the otic vesicle and the limb mesenchyme. The putative roles of SIX1 with respect to POAG, high tension glaucoma, and NTG are based on association between some SIX1 sequence variations and these phenotypes (S. Y. Lu et al, 2019). Specific associations with IOP were also reported (Y. Chen et al, 2015).…”

Section: Transcription Factorsmentioning

confidence: 99%

Insights into the regulatory molecules involved in glaucoma pathogenesis

Moazzeni

Khani

Elahi

2020

American J of Med Genetics Pt C

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Glaucoma is an important cause of irreversible blindness, characterized by optic nerve anomalies. Increased intraocular pressure (IOP) and aging are major risk factors. Retinal ganglion cells and trabecular meshwork cells are certainly involved in the etiology of glaucoma. Glaucoma is usually a complex disease, and various genes and functions may contribute to its etiology. Among these may be genes that encode regulatory molecules. In this review, regulatory molecules including 18 transcription factors (TFs), 195 microRNAs (miRNAs), 106 long noncoding RNAs (lncRNAs), and two circular RNAs (circRNAs) that are reasonable candidates for having roles in glaucoma pathogenesis are described. The targets of the regulators are reported. Glaucomarelated features including apoptosis, stress responses, immune functions, ECM properties, IOP, and eye development are affected by the targeted genes. The targeted genes that are frequently targeted by multiple regulators most often affect apoptosis and the related features of cell death and cell survival. BCL2, CDKN1A, and TP53 are among the frequent targets of three types of glaucoma-relevant regulators, TFs, miRNAs, and lncRNAs. TP53 was itself identified as a glaucoma-relevant TF. Several of the glaucoma-relevant TFs are themselves among frequent targets of regulatory molecules, which is consistent with existence of a complex network involved in glaucoma pathogenesis.

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Association of Polymorphisms at theSIX1-SIX6Locus With Primary Open-Angle Glaucoma

Cited by 15 publications

References 57 publications

Age-dependent regional retinal nerve fibre changes in SIX1/SIX6 polymorphism

Age-dependent regional retinal nerve fibre changes in SIX1/SIX6 polymorphism

The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

Insights into the regulatory molecules involved in glaucoma pathogenesis

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