Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Hauser, Michael A.; Allingham, R. Rand; Aung, Tin; Heide, Carly J. van der; Taylor, Kent D.; Rotter, Jerome I.; Wang, Shih‐Hsiu J.; Bonnemaijer, Pieter W.M.; Williams, Susan E.; Abdullahi, Sadiq M; Abu-Amero, Khaled K.; Anderson, Michael G.; Akafo, Stephen; Alhassan, Mahmoud B; Asimadu, Ifeoma N; Ayyagari, Radha; Bakayoko, Saydou; Nyamsi, Prisca Biangoup; Bowden, Donald W.; Bromley, William; Budenz, Donald L.; Carmichael, Trevor; Challa, Pratap; Chen, Yii‐Der Ida; Chuka-Okosa, CM; Bailey, Jessica N. Cooke; Costa, Vital Paulino; Cruz, Dianne A.; DuBiner, Harvey; Ervin, John F.; Feldman, Robert M.; Flamme-Wiese, Miles J.; Gaasterland, Douglas E.; Garnai, Sarah J.; Girkin, Christopher A.; Guirou, Nouhoum; Guo, Xiuqing; Haines, Jonathan L.; Hammond, Christopher J; Herndon, Leon W.; Hoffmann, Thomas J.; Hulette, Christine M.; Hydara, Abba; Igo, Robert P.; Jorgenson, Eric; Kabwe, Joyce; Kilangalanga, Ngoy Janvier; Kizor-Akaraiwe, Nkiru; Kuchtey, Rachel W.; Lamari, Hasnaa; Li, Zheng; Liebmann, Jeffrey M.; Liu, Yutao; Loos, Ruth J.F.; Melo, Mônica Barbosa de; Moroi, Sayoko E.; Msosa, Joseph; Mullins, Robert F.; Nadkarni, Girish N.; Napo, Abdoulaye; Ng, Maggie C. Y.; Nunes, Hugo Freire; Obeng-Nyarkoh, E; Okeke, Anthony; Okeke, Suhanya; Olaniyi, Olusegun B.; Olawoye, Olusola; Oliveira, Mariana Borges; Pasquale, Louise R.; Perez-Grossmann, Rodolfo A.; Pericak‐Vance, Margaret A.; Qin, Xue; Ramsay, Michèle; Resnikoff, Serge; Richards, Julia E.; Schimiti, Rui Barroso; Sim, Kar Seng; Sponsel, William Eric; Svidnicki, Paulo Vinícius; Thiadens, Alberta A H J; Uche, NJ; Duijn, Cornelia M. van; Vasconcellos, José Paulo Cabral de; Wiggs, Janey L.; Zangwill, Linda M.; Risch, Neil; Miléa, Dan; Ashaye, Adeyinka; Klaver, Caroline C W; Weinreb, Robert N.; Koch, Allison E Ashley; Fingert, John H.; Khor, Chiea Chuen

doi:10.1001/jama.2019.16161

Cited by 48 publications

(18 citation statements)

References 39 publications

(59 reference statements)

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“…In this study they demonstrated that APBB2 rs59892895T > C was associated with POAG (OR 1.32, 95%CI: 1.20–1.46, p = 2 × 10 −8 ). Additionally, they noted that this SNP was only present in AD populations, and had a frequency <0.1% in populations of ED or Asian ancestry [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned previously in the AD population section, the GWAS conducted by Hauser, et al included patients of AD mixed with individuals from Saudi Arabia identifying APBB2 rs59892895T > C as associated with POAG in the AD/Saudi Arabian populations [ 48 ]. Currently there is a lack of large uniform genetic data on ME populations and POAG, with available data often segregated to specific countries within the ME or with admixture of other population genetics.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

Zukerman

Harris

Vercellin

et al. 2020

Genes

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Glaucoma, the world’s leading cause of irreversible blindness, is a complex disease, with differential presentation as well as ethnic and geographic disparities. The multifactorial nature of glaucoma complicates the study of genetics and genetic involvement in the disease process. This review synthesizes the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, with the only treatable risk factor (RF) being the reduction of intraocular pressure (IOP). Genes associated with elevated IOP or POAG risk include: ABCA1, AFAP1, ARHGEF12, ATXN2, CAV1, CDKN2B-AS1, FOXC1, GAS7, GMDS, SIX1/SIX6, TMCO1, and TXNRD2. However, there are variations in RF and genetic factors based on ethnic and geographic differences; it is clear that unified molecular pathways accounting for POAG pathogenesis remain uncertain, although inflammation and senescence likely play an important role. There are similar ethnic and geographic complexities in primary angle closure glaucoma (PACG), but several genes have been associated with this disorder, including MMP9, HGF, HSP70, MFRP, and eNOS. In exfoliation glaucoma (XFG), genes implicated include LOXL1, CACNA1A, POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A. Despite tremendous progress, major gaps remain in resolving the genetic architecture for the various glaucoma subtypes across ancestries. Large scale carefully designed studies are required to advance understanding of genetic loci as RF in glaucoma pathophysiology and to improve diagnosis and treatment options.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

Zukerman

Harris

Vercellin

et al. 2020

Genes

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“…Based on the pooled data, the rs449647 of the APOE gene had a significant association with POAG in the allelic, homozygote, heterozygote, and dominant comparisons. In a more recent GWAS study on 2320 patients of African ancestry with POAG and on 2121 without POAG, 4 the Aß A4 precursor protein-binding family B member 2 (APBB2), located on chromosome 4 with the variant rs59892895T>C, was significantly associated with POAG (P = 2 x 10 −8 ). Each copy of the rs59892895*C risk allele, most frequently found in individuals of African ancestry compared to those of European or Asian ancestry, was associated with an increased risk of POAG.…”

Section: The Role Of Apolipoprotein E (Apoe) Gene In Primary Open-angmentioning

confidence: 99%

“… 2 , 3 Some AD genes, such as Apolipoprotein E (APOE), have been shown to increase the risk for POAG. 4 , 5 Similar to the chronic insult of repetitive head trauma in chronic traumatic encephalopathy (CTE), 3 recurrent IOP elevations might cause repetitive compressive compromise to the optic nerve head. These repetitive forces to the optic nerve head might potentially lead to tau accumulation, altered phosphorylation, and mis-sorting in glaucomatous neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Glaucoma as Neurodegeneration in the Brain

Chan¹,

Chan

Sadun³

2021

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Glaucoma, a group of diseases characterized by progressive optic nerve degeneration that results in irreversible blindness, can be considered a neurodegenerative disorder of both the eye and the brain. Increasing evidence from human and animal studies have shown that glaucoma shares some common neurodegenerative pathways with Alzheimer's disease (AD) and other tauopathies, such as chronic traumatic encephalopathy (CTE) and frontotemporal dementia. This hypothesis is based on the focal adhesion pathway hypothesis and the spreading hypothesis of tau. Not only has the Apolipoprotein E (APOE) gene been shown to be associated with AD, but also with primary open angle glaucoma (POAG). This review will highlight the relevant literature in the past 20 years from PubMed that show the pathogenic overlap between POAG and AD. Neurodegenerative pathways that contribute to transsynaptic neurodegeneration in AD and other tauopathies might also be similar to those in glaucomatous neurodegeneration.

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“…A majority of glaucoma cases are attributed to primary open-angle glaucoma (POAG), for which IOP elevation lacks an obvious physical cause ( Quigley and Broman, 2006 ). Recently, genome-wide association studies (GWAS) have improved understanding of the genetic basis of POAG by implicating more than 70 loci ( Bonnemaijer et al, 2018 ; Choquet et al, 2018 , 2020 ; Genetics of Glaucoma in People of African Descent Consortium et al, 2019 ; Khawaja et al, 2018 ; MacGregor et al, 2018 ; Taylor et al, 2019 ; Youngblood et al, 2019 ). Research that defines how these genes affect IOP is expected to yield new drug targets and improved treatments for lowering IOP ( Choquet et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice

Tolman

Balasubramanian

Macalinao

et al. 2021

Disease Models &Amp; Mechanisms

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Variants in the LIM homeobox transcription factor 1-beta gene (LMX1B) predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1bV265D (also known as Lmx1bIcst) allele onto the C57BL/6J (B6), 129/Sj (129), C3A/BLiA-Pde6b+/J (C3H), and DBA/2J-Gpnmb+ (D2-G) mouse strain backgrounds. Strain background had a significant effect on the onset and severity of ocular phenotypes in Lmx1bV265D/+ mutant mice. Mice of the B6 background were the most susceptible to developing an abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands, and corneal abnormalities) and glaucomatous nerve damage. In contrast, Lmx1bV265D mice of the 129 background were the most resistant to developing anterior segment abnormalities, had less severe IOP elevation than B6 mutants at young ages, and showed no detectable nerve damage. To identify genetic modifiers of susceptibility to Lmx1bV265D-induced glaucoma-associated phenotypes, we performed a mapping cross between mice of the B6 (susceptible) and 129 (resistant) backgrounds. We identified a modifier locus on Chromosome 18, with the 129 allele(s) substantially lessening severity of ocular phenotypes, as confirmed by congenic analysis. By demonstrating a clear effect of genetic background in modulating Lmx1b-induced phenotypes, providing a panel of strains with different phenotypic severities, and identifying a modifier locus, this study lays a foundation for better understanding the roles of LMX1B in glaucoma with the goal of developing new treatments.

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Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Cited by 48 publications

References 39 publications

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

Glaucoma as Neurodegeneration in the Brain

Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice

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