A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study

Khawaja, Anthony P.; Chan, Michelle; Yip, Jennifer; Broadway, David C; Garway-Heath, David; Viswanathan, Ananth C.; Luben, Robert; Hayat, Shabina; Hauser, Michael A.; Wareham, Nicholas J.; Khaw, Kay‐Tee; Fortune, Brad; Allingham, R. Rand; Foster, Paul J.

doi:10.1097/ijg.0000000000001026

Cited by 12 publications

(12 citation statements)

References 39 publications

(57 reference statements)

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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%

“…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 copy of the risk allele was associated with significant thinning of global peripapillary RNFL for rs33912345 in large European 20 and Singaporean 21 cohorts but not in a Japanese population 22 . In addition, the above studies also partitioned global RNFL into inferior, nasal, superior and temporal quadrants and found significant thinning with each copy of the rs33912345 risk allele and the superior as well as the inferior quadrants in the Singaporean study 21 but significant thinning was found in the temporal and inferior quadrants in the Japanese study 22 .…”

Section: Introductionmentioning

confidence: 91%

“…To date, the association between RNFL thickness and SIX1/SIX6 variants have only been reported in older individuals (mean age > 50 years) [20][21][22][23] . Hence it is not known whether these genetic variants exert their effects in younger individuals.…”

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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%

Section: Introductionmentioning

confidence: 91%

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

Charng

Simcoe

Sanfilippo

et al. 2020

Sci Rep

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“…To improve understanding of how genes associated with glaucoma contribute to disease pathogenesis, we mapped their expression by the 19 cell types in our atlas. We included both known monogenic causes (Mendelian genes) and genes implicated as risk factors in GWAS studies (Wiggs and Pasquale, 2017;Lewis et al,2017;Choquet et al, 2018;Gao et al, 2018;Khawaja et al, 2018;Macgregor et al, 2018;Sears et al, 2019;Youngblood et al, 2019;Krumbiegel et al,2019). Mendelian genes assessed were ANGPT1, ANGPT2,CPAMD8,CYP1B1,FOXC1,LOXL1,LTBP2,MYOC,OPTN,PITX2,TEK (TIE2), and TBK1.…”

Section: Cell-type Specific Expression Patterns Of Glaucoma-associatementioning

confidence: 99%

“…We then used this cell atlas in two ways. First, we assessed expression in each cell type of genes that have been implicated in glaucoma, either as causal genes with Mendelian inheritance or as susceptibility loci identified in genome-wide association studies (GWAS) (Wiggs and Pasquale, 2017;Lewis et al,2017;Choquet et al, 2018;Gao et al, 2018;Khawaja et al, 2018;Macgregor et al, 2018;Sears et al, 2019;Youngblood et al, 2019;Krumbiegel et al,2019), and compared expression levels in cell types of the outflow pathways to those in retinal RGCs and retinal glia (Yan et al, in prep). We found that genes associated with elevated IOP were more likely to be preferentially expressed in the anterior segment, whereas those associated with normal tension glaucoma were more likely to be expressed predominantly in the retina.…”

Section: Introductionmentioning

confidence: 99%

Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insights into Glaucoma Pathogenesis

Zyl

Yan

McAdams

et al. 2020

Preprint

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ABSTRACTIncreased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells that carry information from the eye to the brain; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye, called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single cell RNA sequencing (scRNA-seq). From ∼24,000 single cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (Macaca fascicularis), rhesus macaque (Macaca mulatta), pig (Sus scrofa) and mouse (Mus musculus). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma, and for using model systems to assess mechanisms and potential interventions.

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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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A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study

Abstract: The protein-coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans.

Cited by 12 publications

References 39 publications

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

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

Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insights into Glaucoma Pathogenesis

Insights into the regulatory molecules involved in glaucoma pathogenesis

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