Highly Penetrant Alleles in Age-Related Macular Degeneration

Hollander, Anneke I. den

doi:10.1101/cshperspect.a017202

Cited by 20 publications

(13 citation statements)

References 76 publications

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“…At the other end of the spectrum of ocular conditions having a genetic component lies age-related macular degeneration (AMD), another retinal disease affecting people aged 50 and over. AMD is a bona fide complex disease with a relatively high prevalence (1 in 13 individuals), favored by the presence of polymorphic SNPs, highly-penetrant rare variants, and environmental factors 10 . Between these two pillars of inheritance, there is an intermediate zone, consisting in a few examples for which extremely rare mutations in more than one gene are associated with Bardet-Biedl syndrome, a retinal ciliopathy displaying sometimes digenic triallelic inheritance [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

Nikopoulos

Cisarova

Koskiniemi-Kuendig

et al. 2018

Preprint

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Section: Introductionmentioning

confidence: 99%

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

Nikopoulos

Cisarova

Koskiniemi-Kuendig

et al. 2018

Preprint

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“…The development of AMD depends on a complex interplay of risk factors, which include age, genetics, and behavior 2 . Behavioral factors such as smoking 3 , diet 4 , and sunlight exposure 5 6 7 each can contribute to the development of AMD; and genetic variations in genes involved in the complement system, as well as others have been found to be associated with risk for disease or risk of progression from early to late AMD 8 9 . Overall, the data suggest that AMD is a progressive neurodegenerative disease involving inflammation 10 , and in particular an inflammatory immune response 11 .…”

mentioning

confidence: 99%

Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells

Coughlin

Schnabolk

Joseph

et al. 2016

Sci Rep

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Neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). An overactive complement system is associated with AMD pathogenesis, and serum pro-inflammatory cytokines, including IL-17, are elevated in AMD patients. IL-17 is produced by complement C5a-receptor-expressing T-cells. In murine CNV, infiltrating γδT- rather than Th17-cells produce the IL-17 measurable in lesioned eyes. Here we asked whether C5a generated locally in response to CNV recruits IL-17-producing T-cells to the eye. CNV lesions were generated using laser photocoagulation and quantified by imaging; T-lymphocytes were characterized by QRT-PCR. CNV resulted in an increase in splenic IL-17-producing γδT- and Th17-cells; yet in the CNV eye, only elevated levels of γδT-cells were observed. Systemic administration of anti-C5- or anti-C5a-blocking antibodies blunted the CNV-induced production of splenic Th17- and γδT-cells, reduced CNV size and eliminated ocular γδT-cell infiltration. In ARPE-19 cell monolayers, IL-17 triggered a pro-inflammatory state; and splenocyte proliferation was elevated in response to ocular proteins. Thus, we demonstrated that CNV lesions trigger a systemic immune response, augmenting local ocular inflammation via the infiltration of IL-17-producing γδT-cells, which are presumably recruited to the eye in a C5a-dependent manner. Understanding the complexity of complement-mediated pathological mechanisms will aid in the development of an AMD treatment.

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“…The interplay between phenotype, genotype [103,104], environmental [5] or lifestyle [105] are all being considered, but combination of these factors result in a complex interactions. In addition, recent reviews summarized the available potential biomarkers from serum, plasma, aqueous humour, vitreous, and urine of AMD patients [63,64].…”

Section: Potential Use Of Non-genomic Tests and Modalities As Biomarkmentioning

confidence: 99%

Precision medicine for age-related macular degeneration: current developments and prospects

Biarnés

Vassilev

Nogoceke

et al. 2018

Expert Review of Precision Medicine and Drug Development

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Introduction: With the ageing population, diseases such as age-related macular degeneration (AMD) will become more prevalent. This will increase demand for provision of care on affected individuals, society and the healthcare system. To develop the best, individually tailored treatment for every patient, however, remains challenging. Areas covered: Recent identifications of interactions between environmental, lifestyle, genetic and non-genetic factors opened the potential for developing personalised approaches for the prevention and treatment of AMD. In this review, we will discuss the implications of these interactions for early to late disease stage conversion, for neovascularization and cell atrophy. We will put the findings of recent studies within the context of the regulatory framework requirements surrounding the development of personalised medicine approach to AMD. Expert Opinion: Precision medicine is now at a stage that it has its theoretical framework in place for the management of risk for patients with AMD requiring early diagnosis and timely treatment as several key components for such an approach are now clearly identified and are being applied to clinical developments successfully.

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Highly Penetrant Alleles in Age-Related Macular Degeneration

Cited by 20 publications

References 76 publications

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells

Precision medicine for age-related macular degeneration: current developments and prospects

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