Genetic Association Analysis of Drusen Progression

Grinsven, Mark J. J. P. van; Li, Chun; Brantley, Milam A.; McGrath, Josephine A.; Scott, William K.; Schwartz, Stephen G.; Kovach, Jaclyn L.; Pericak‐Vance, Margaret A.; Sánchez, Clara I.; Haines, Jonathan L.

doi:10.1167/iovs.15-18571

Cited by 16 publications

(18 citation statements)

References 51 publications

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“…Multiple studies have also shown that AMD-associated genetic variants are associated with disease progression, but in most studies only a subset of AMD-associated variants were used 13–19 . In addition, the total number of AMD-associated variants is also known to be associated with the clinical disease stage, which was also confirmed in our study where the GRS was associated with the drusen coverage 16,24 . According to a recent prospective cohort, genetic variants only provide a limited additional predicting power when the clinical grading stage at baseline is included as predictor 15 .…”

Section: Discussionsupporting

confidence: 89%

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

Heesterbeek

Acar

Groenewoud

et al. 2019

Sci Rep

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Several prediction models for progression of age-related macular degeneration (AMD) have been developed, but the added value of using genetic information in those models in addition to clinical characteristics is ambiguous. In this prospective cohort study, we explored the added value of genetics using a genetic risk score (GRS) based on 52 AMD-associated variants, in addition to the clinical severity grading at baseline as quantified by validated drusen detection software, to predict disease progression in 177 AMD patients after 6.5 years follow-up. The GRS was strongly associated with the drusen coverage at baseline (P < 0.001) and both the GRS and drusen coverage were associated with disease progression. When the GRS was added as predictor in addition to the drusen coverage, R 2 increased from 0.46 to 0.56. This improvement by the GRS was predominantly seen in patients with a drusen coverage <15%. In patients with a larger drusen coverage, the GRS had less added value to predict progression. Thus, genetic information has added value over clinical characteristics in predicting disease progression in AMD, but only in patients with a less severe disease stage. Patients with a high GRS should be made aware of their risk and could be selected for clinical trials for arresting progression.

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Section: Discussionsupporting

confidence: 89%

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

Heesterbeek

Acar

Groenewoud

et al. 2019

Sci Rep

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“… 20 A longitudinal analysis of a small subgroup of the AREDS sample ( N = 75) did not find an association between a genetic score, including 19 common risk variants, and progression of drusen based on color photos assessed with an automated algorithm, possibly owing to low power. 29 We have previously shown that carriers of the rare variant CFH R1210C have a higher drusen burden in the macular and extra-macular locations, 26 , 30 but no previous studies have explored the impact of this high impact genetic variant or the high-risk rare C3 variant 31 on drusen size progression. Both of these rare variants were shown to be associated with drusen growth in this prospective study.…”

Section: Discussionmentioning

confidence: 99%

Genetic Susceptibility, Diet Quality, and Two-Step Progression in Drusen Size

Merle

Rosner

Seddon

2020

Invest. Ophthalmol. Vis. Sci.

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To investigate the relationship of growth in drusen size with genetic susceptibility and adherence to the alternate Mediterranean diet. METHODS. Participants in this analysis had complete ocular, genetic, and dietary data with mean follow-up time of 10.2 years in the Age-Related Eye Disease database. Maximal drusen size was graded on an ordinal scale and two-step progression was determined. A genetic risk score using variants associated with advanced AMD and derived from a stepwise regression model yielded 11 variants in 8 genes. Adherence to the alternate Mediterranean diet was assessed using a nine-component score based on intake of vegetables, fruits, legumes, whole cereals, fish, meat, nuts, alcohol, and monounsaturatedto-saturated fatty acids ratio. Multivariate Cox proportional hazards models were used. RESULTS. Among 3023 eligible eyes, 19% had drusen growth. In the stepwise selection, common and rare risk alleles for CFH Y402H, CFH rs1410996, CFH R1210C, C3 R102G, C3 K155Q, and ARMS2/HTRA1, as well as VEGF-A, TIMP3, NPLOC4, and HSPH1 variants were significantly associated with 2-step progression in drusen size, and the C2 E318D protective allele conferred decreased risk, adjusting for other covariates. A higher genetic risk score conferred a higher risk (hazard ratio per 1-unit increase, 2.68; 95% confidence interval, 2.23-3.23; P < 0.001), and a medium/high adherence to alternate Mediterranean diet score (4-9) tended to lower risk (hazard ratio, 0.83; 95% confidence interval, 0.68-0.99; P = 0.049), adjusting for all covariates. CONCLUSIONS. Genetic susceptibility was independently related to drusen growth. A Mediterranean-style diet with healthful nutrient-rich foods (fruits, vegetables, legumes and fish), may reduce enlargement of drusen, the hallmark of AMD.

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“…The patients who have intermediate drusen but at least one drusen with >125 micron were considered as AREDS 3. Patients who appeared with wet and GA phenotypes were included in ADRES 4 and AREDS 5 [Hoffman et al, ].…”

Section: Methodsmentioning

confidence: 99%

Serum Levels of TIMP-3, LIPC, IER3, and SLC16A8 in CFH-Negative AMD Cases

et al. 2017

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AMD is a complex eye disease predominantly occurring in aged population. Till now about 53 genetic loci have been found to be associated with the AMD pathology. AMD pathogenesis is being increasingly known to progress through mechanisms independent of the CFH mediated pathway. Therefore, our aim for current study was to examine the genes by analyzing their expression levels in AMD. We recruited about 50 AMD and same number of age matched controls. We analyzed the CFH duplication and deletion by multiplex ligation probe amplification (MLPA) and found no duplication and deletion in CFH gene in AMD patients. We also estimated the IER-3, SLC16A8, LIPC, and TIMP-3 expression levels in both CFH-negative AMD cases (i.e. no duplication and deletion in CFH gene) besides examining these in AMD and controls. We found that the expression level of LIPC, SLC16A8, and TIMP-3 was significantly associated with AMD pathology in both groups (LIPC: P = 0.008, SLC16A8: P < 0.001, TIMP-3: P < 0.001, respectively). However, we did not find any significant difference in IER-3 levels in AMD and controls. Therefore, the evidence from current study, suggests that AMD pathology may be mediated through mechanistic pathways linked to other genetic loci. J. Cell. Biochem. 118: 2087-2095, 2017. © 2016 Wiley Periodicals, Inc.

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Genetic Association Analysis of Drusen Progression

Cited by 16 publications

References 51 publications

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

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

Genetic Susceptibility, Diet Quality, and Two-Step Progression in Drusen Size

Serum Levels of TIMP-3, LIPC, IER3, and SLC16A8 in CFH-Negative AMD Cases

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