Genetic Determinants of Intraocular Pressure

Xu, Zihe; Hysi, Pirro G.; Khawaja, Anthony P

doi:10.1146/annurev-vision-031021-095225

Cited by 10 publications

(9 citation statements)

References 116 publications

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“…Current glaucoma drugs target lowering IOP. Previous studies using directly genotyped and imputed genetic data have uncovered common and some lowfrequency variants for IOP [1][2][3][4][5][6] . Identifying rare variants that contribute to IOP will help uncover the biological mechanisms regulating this trait and provide improved understanding of IOP regulation and potential therapeutic targets for managing IOP and glaucoma.Genome-wide association studies (GWAS) have identified over 190 genetic loci associated with IOP 1-4 .…”

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confidence: 99%

Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma

2022

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Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 110,260 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. About half of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent participants (n = 312,825). We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP and uncovered potential therapeutic targets for glaucoma.

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confidence: 99%

Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma

2022

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“…Studies have found that the heritability of IOP ranges from 0.35 to 0.67, depending on the study design ( Klein et al, 2004 ; Chang et al, 2005 ; van Koolwijk et al, 2007 ; Carbonaro et al, 2009 ; Zheng et al, 2009 ; Sanfilippo et al, 2010 ; Asefa et al, 2019 ). Identifying genetic factors that contribute to IOP aid in uncovering the biological mechanisms regulating this trait ( Ojha et al, 2013 ; Xu et al, 2021 ), which provides new management avenues for IOP and POAG.…”

Section: Introductionmentioning

confidence: 99%

10 Years of GWAS in intraocular pressure

et al. 2023

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Intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, the leading cause of irreversible blindness worldwide. In this review, we summarize the findings of genome-wide association studies (GWASs) of IOP published in the past 10 years and prior to December 2022. Over 190 genetic loci and candidate genes associated with IOP have been uncovered through GWASs, although most of these studies were conducted in subjects of European and Asian ancestries. We also discuss how these common variants have been used to derive polygenic risk scores for predicting IOP and glaucoma, and to infer causal relationship with other traits and conditions through Mendelian randomization. Additionally, we summarize the findings from a recent large-scale exome-wide association study (ExWAS) that identified rare variants associated with IOP in 40 novel genes, six of which are drug targets for clinical treatment or are being evaluated in clinical trials. Finally, we discuss the need for future genetic studies of IOP to include individuals from understudied populations, including Latinos and Africans, in order to fully characterize the genetic architecture of IOP.

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“…Moreover, the number of GC patients is expected to reach 111.8 million by 2040 (Allison et al, 2020). There are several known risk factors for GC, such as high intraocular pressure (IOP), a family history, high myopia, and cardiovascular disease (Jonas et al, 2017b; Wang et al, 2021); among which, elevated IOP remains the only recognized risk factor for GC (Xu et al, 2021). A lowering of IOP is also the only method that has been verified as effective for preventing GC progression (Lin et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Insights into CD154‐mediated pathways in ocular hypertensive glaucoma: The role of Müller cells and P2X7 in retinal neuroprotection and therapeutic potential

Liu

Nie

et al. 2023

Cell Biology International

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An elevation of pathologic intraocular pressure (IOP) is the greatest risk factor for glaucoma. CD154 has been reported to bind to CD40 expressed by orbital fibroblasts and be involved in immune and inflammatory responses. However, the function and mechanism of CD154 in ocular hypertensive glaucoma (OHG) are not fully understood. We isolated and characterized Müller cells and subsequently examined the effect of CD154 on ATP release from those cells. After being cocultured with CD154-pretreated Müller cells, retinal ganglion cells (RGCs) were treated with P2X7 siRNAs or a P2X7 inhibitor. Furthermore, mouse models of glaucoma (GC) were injected with P2X7 shRNA. p21, p53, and P2X7 expression were examined, and cellular senescence and apoptosis were detected by β-Gal and TUNEL staining, retinal pathology was examined by H&E staining, and CD154 and β-Gal expression were detected by ELISA. CD154 induced ATP release from Müller cells and accelerated the senescence and apoptosis of RGCs that had been cocultured with Müller cells. We also found that treatment with P2X7 could attenuate the senescence and apoptosis of RGCs mediated by Müller cells pretreated with CD154. In vivo studies in GC model mice verified that P2X7 silencing attenuated pathological damage and prevented the senescence and apoptosis of retinal tissue. The study demonstrates how CD154 accelerates the aging and apoptosis of RGCs by co-cultivating Müller cells pretreated with CD154 in OHG. The research implies that CD154 has the potential to become a new therapeutic target for ocular hypertension glaucoma, providing a new research direction for its treatment.

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Genetic Determinants of Intraocular Pressure

Cited by 10 publications

References 116 publications

Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma

Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma

10 Years of GWAS in intraocular pressure

Insights into CD154‐mediated pathways in ocular hypertensive glaucoma: The role of Müller cells and P2X7 in retinal neuroprotection and therapeutic potential

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