Genetic risk score has added value over initial clinical grading stage in predicting disease progression in age-related macular degeneration

Heesterbeek, Thomas J.; Acar, İlhan E.; Groenewoud, J.M.M.; Liefers, Bart; Sánchez, Clara I.; Hoyng, Carel B.; Pauleikhoff, Daniel; Hense, Hans Werner; Hollander, Anneke I. den

doi:10.1038/s41598-019-43144-3

Cited by 24 publications

(23 citation statements)

References 34 publications

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“…65 Another PRS comprising all 52 AMD-associated variants was applied to an independent prospective German cohort of AMD patients, and was associated with drusen load in agreement with earlier reports from the AREDS cohort. 66,67 Moreover, the 52-variant PRS was associated with drusen progression in individuals with low drusen load at baseline, and both drusen and AMD progression to late disease in those with intermediate drusen load during the mean 6.5 years of follow-up. 66 Seddon and Rosner 68 have incorporated 13 AMDassociated risk loci into a predictive model including known demographic and ocular risk factors (baseline AMD grading) in the AREDS cohort and further validated this in an independent longitudinal AMD cohort.…”

Section: Age-related Macular Degenerationmentioning

confidence: 93%

Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology

Qassim

Souzeau

Hollitt

et al. 2021

Trans. Vis. Sci. Tech.

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Combining genetic and clinical data into an informative risk prediction profile has been an important ambition of personalized medicine. Single-nucleotide polymorphisms are commonly found throughout the genome and account for the majority of interindividual genetic variation. To date, genome-wide association studies have led to the discovery of thousands of disease-associated loci, including across dozens of ophthalmic diseases and traits. However, compared with the clinical utility of identifying rare Mendelian variants, the translation of these results to clinical practice has so far been limited because such variants are found commonly in the population, and individually account for a very small risk. Recently, combining large numbers of these genetic variants into polygenic risk scores (PRS) has shown clinically meaningful risk prediction across several common diseases. PRS have the potential to translate the discovery of common risk variants into individualized disease risk prediction, prognostication, and may enable targeted treatments. In this context, we review the clinical utility of PRS in three common, genetically complex ophthalmic conditions: primary open angle glaucoma, age-related macular degeneration, and myopia.Translational Relevance: Common genetic variants can be used to effectively stratify the risk of disease development and progression and may be used to guide screening, triaging, monitoring, or treatment thresholds.

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Section: Age-related Macular Degenerationmentioning

confidence: 93%

Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology

Qassim

Souzeau

Hollitt

et al. 2021

Trans. Vis. Sci. Tech.

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“…When individual drusen decrease in size, they may result in no residual anatomic defects or they may evolve into GA or nAMD . The total number of drusen or measured drusen area or volume, are risk factors for the progression to GA and nAMD . Also, the location of the drusen is of predictive value for disease progression, since eyes with drusen near the fovea have a higher probability of developing late AMD compared to eyes with drusen outside the fovea .…”

Section: Phenotypic Risk Factorsmentioning

confidence: 99%

Risk factors for progression of age‐related macular degeneration

Heesterbeek

Lorés‐Motta

Hoyng

et al. 2020

Ophthalmic Physiologic Optic

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257

224

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Purpose Age‐related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. The rate of disease progression can vary among individuals and has been associated with multiple risk factors. In this review, we provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors, and propose the most consistently identified risk factors for disease progression in AMD based on these studies. Finally, we describe the potential use of these risk factors for personalised healthcare. Recent findings While phenotypic risk factors such as drusen and pigment abnormalities become more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors are more valuable at earlier disease stages. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression, while other factors such as sex, body mass index (BMI) and education are less often associated. Of all known AMD variants, variants that are most consistently reported with disease progression are rs10922109 and rs570618 in CFH, rs116503776 in C2/CFB/SKIV2L, rs3750846 in ARMS2/HTRA1 and rs2230199 in C3. However, it seems likely that other AMD variants also contribute to disease progression but to a lesser extent. Rare variants have probably a large effect on disease progression in highly affected families. Furthermore, current prediction models do not include molecular risk factors, while these factors can be measured accurately in the blood. Possible promising molecular risk factors are High‐Density Lipoprotein Cholesterol (HDL‐C), Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), zeaxanthin and lutein. Summary Phenotypic, demographic, environmental, genetic and molecular risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and is dependent on their current disease stage. Future prediction models should include a wider set of genetic variants to determine the genetic risk more accurately, and rare variants should be taken into account in highly affected families. In addition, adding molecular factors in prediction models may lead to preventive strategies and personalised advice.

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“…In primary open-angle glaucoma, a higher PRS is associated with several endophenotypes, including earlier disease onset, intraocular pressure, and optic disc vertical cup-to-disc ratio [ 27 , 28 , 29 , 30 ]. However, few reports demonstrated the association of a PRS with endophenotypes in exudative AMD [ 11 ]. The present study demonstrated that PRSs can be informative in predicting the treatment response in the context of exudative AMD, though further studies are required to elucidate the exact relationship between such PRSs, and clinical features and treatment response.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Heesterbeek et al [ 11 ] demonstrated that a polygenic risk score (PRS) can contribute to predicting AMD progression ( n = 177). However, to date, no reports describe research investigating the relationship between PRS and treatment outcomes in the context of VEGF-inhibitor-based treatment of exudative AMD.…”

Section: Introductionmentioning

confidence: 99%

Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration

et al. 2020

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We investigated whether polygenic risk score (PRS) was associated with one-year outcome of as-needed aflibercept therapy for exudative age-related macular degeneration (AMD), including AMD (n = 129) and polypoidal choroidal vasculopathy (n = 132). A total of 261 patients were treated with as-needed intravitreal aflibercept injection (IAI) after three monthly IAIs and the completion of a one-year follow-up. One hundred and seventy-two healthy volunteers served as controls. Genotyping of ARMS2 A69S (rs10490924), CFH I62V (rs800292), SKIV2L-C2-CFB (rs429608), C3 (rs2241394), ADAMTS-9 (rs6795735) and CETP (rs3764261) was performed for all participants. A total of 63 PRSs were quantified. There was a positive association between the PRS involving ARMS2, CFH, C3, and ADAMTS-9 and best-corrected visual acuity at twelve months (p = 0.046, multiple regression analysis). When comparing PRSs of patients requiring retreatment and of patients without retreatment, 35 PRSs were significantly greater in patients requiring retreatment than in patients without requiring retreatment, with the PRS involving ARMS2 and CFH being most significantly associated (p = 1.6 × 10−4). The number of additional injections was significantly associated with 40 PRSs and the PRS involving ARMS2 and CFH showed a most significant p-value (p = 2.42 × 10−6). Constructing a PRS using a combination with high-risk variants might be informative for predicting the response to IAI for exudative AMD.

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Genetic risk score has added value over initial clinical grading stage in predicting disease progression in age-related macular degeneration

Cited by 24 publications

References 34 publications

Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology

Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology

Risk factors for progression of age‐related macular degeneration

Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration

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