Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration
Open accessAbstract
Aging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals. Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD). Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges. We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.
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Written from the paper’s full text.
TL;DR
This review synthesizes genetic, epidemiologic, pathologic, and animal-model evidence on age-related macular degeneration (AMD) and proposes a “multiple-hit” model in which genetic susceptibility, aging-related cellular decline, and environmental exposures combine to cross a disease threshold. It highlights complement pathway variants (especially CFH) and ARMS2/HTRA1 as major genetic contributors and discusses implications for prevention and anti-VEGF treatment.
Key findings
- AMD is a leading cause of severe incurable vision impairment; advanced AMD prevalence rises from ~0.2% at ages 55–64 to 13% in those older than 85 years, and in the USA approximately 1.75 million people aged ≥40 have advanced AMD and another 7.3 million have intermediate AMD.
- Genetic factors are substantial: twin studies suggest as much as 71% of variation in overall AMD severity is genetically determined; the strongest signals are in the complement pathway (CFH, C2/CFB, C3, CFI) and at ARMS2/HTRA1.
- Environmental and modifiable risks include smoking, which typically confers about a two-fold increased risk of advanced AMD; AREDS high-dose antioxidant vitamins plus zinc/copper slowed progression to advanced AMD by 25%, with potential to prevent 300,000 individuals from developing advanced AMD over 5 years.
- For neovascular AMD, intravitreal ranibizumab prevented vision loss and improved vision: mean increase of 7 letters in treated patients versus decrease of 10 letters in placebo/sham-injected controls (P < 0.001).
Methods
- Narrative review integrating human genetics (linkage, candidate-gene association, genome-wide association), epidemiology, pathology, aging biology, and mouse models of AMD.
- Uses the AREDS classification of AMD and cites population-based prevalence data, including MESA estimates by race/ethnicity: 2.4% African-American, 4.2% Hispanic, 4.6% Chinese-descent, and 5.4% Caucasian persons aged 45–85 years.
- Main synthesis is an integrated “multiple-hit” model with three stages: initiation by genetic susceptibility, modification by aging-associated changes, and clinical manifestation after environmental triggers.
Limitations
- The paper states that the multiple-hit model is “conceptually convenient” but “obviously might not reflect the full complexity of susceptibility to AMD.”
- It cautions that many candidate-gene association findings are tentative, not as widely replicated, and that publication bias cannot be discounted without large definitive confirmatory studies.
- It notes that no mouse model perfectly mimics AMD in genetic susceptibility, advanced age, and environmental factors, and that human aging-retina expression studies are hampered by difficulty obtaining patient material and inter-individual variability; as a review, it also does not present new primary data or a systematic meta-analysis.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 154 cited sources checked · 0 supported · 0 flagged
- Findingcitation
Initial expression analyses of GFP-tagged rod photoreceptors purified from mouse retinas demonstrate aging-associated changes in genes involved in mitochondrial function, protein degradation, and apoptosis.
“Initial expression analyses of GFP-tagged rod photoreceptors purified from the retinas of mice (5) demonstrate aging-associated changes in genes involved in mitochondrial function, protein degradation, and apoptosis (S. Parapuram & A. Swaroop, unpublished data).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (S. Parapuram & A. Swaroop, unpublished data)
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- Premisecitation
Age is the strongest risk factor associated with the development of AMD.
“Age is the strongest risk factor associated with the development of AMD (3, 112, 140) (Figure 3).”
- Also stated in: § INTEGRATING THE BIOLOGY OF AGING IN STUDIES OF AMD · plain
“Aging is the single strongest risk factor for AMD; hence it is critical to integrate the biology of aging in models of AMD.”
Quote in the paperSubstantial claim0 of 3 sources checked - Also stated in: § INTEGRATING THE BIOLOGY OF AGING IN STUDIES OF AMD · plain
- Premisecitation
Epidemiological studies have revealed differences in the prevalence of advanced AMD among different ethnic groups.
“Epidemiological studies have revealed differences in the prevalence of advanced AMD among different ethnic groups (51, 3, 141).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisenone given
Early pathological changes in AMD include the appearance of basal deposits in Bruch's membrane.
“Early pathological changes in AMD include the appearance of basal deposits in Bruch’s membrane, which is made up of the basement membranes of the RPE and the choriocapillaris.”
Quote in the paperNot a substantial claim - Premisecitation
Biochemical analysis of drusen has identified glycoconjugates and components found in atherosclerotic plaques, including vitronectin, apolipoprotein B and E, alpha-crystallin, complement proteins, and lipids.
“Biochemical analysis of drusen has identified glycoconjugates and components found in atherosclerotic plaques including vitronectin, apolipoprotein B and E, alpha-crystallin, complement proteins, and lipids (32, 106, 115).”
Quote in the paperNot a substantial claim0 of 3 sources checked
- Premisecitation
Basal deposits in Bruch's membrane are of two distinct types: basal laminar deposits between the RPE and basement membrane, and basal linear deposits.
“These deposits are of two distinct types (59): (a) basal laminar deposits between the RPE and basement membrane, and (b) basal linear deposits, which are composed primarily of membraneous material located external to the RPE basement membrane in Bruch’s membrane and are believed to be more specific to AMD (126).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [59] Green WR, 1999, Mol. Vis.
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- cites [126] source
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- Premisecitation
A dose effect of enhanced risk of AMD with increasing number of cigarettes smoked has been reported.
“A dose effect of enhanced risk of AMD with increasing number of cigarettes smoked has also been reported (86).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [86] source
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- Premisecitation
Results from observational, case control, and population-based studies have suggested an association of diet with AMD susceptibility.
“Results from observational, case control, and population-based studies have also suggested an association of diet with AMD susceptibility.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Accumulation of basal deposits together with secondary RPE changes may lead to the formation of drusen.
“Accumulation of these deposits together with secondary RPE changes may lead to the formation of drusen.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The prevalence of AMD phenotypes depends on three key risk factors: environmental factors, advanced age, and genetic susceptibility variants.
“Based on epidemiology and pathobiology, prevalence of AMD phenotypes depends on three key risk factors: environmental factors, advanced age, and genetic susceptibility variants (see Figure 3).”
Quote in the paperSubstantial claim- Rests on an assumption: Late-onset diseases generally result from the interplay between multiple genetic susceptibility factors and environmental components.
- Premisecitation
In AMD, dysfunction and death of macular photoreceptors are responsible for impairment of central vision.
“Though the initial lesions in both GA and CNV involve RPE and Bruch’s membrane pathology, it is the dysfunction and death of macular photoreceptors that are responsible for impairment of central vision in AMD (78).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [78] source
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- Premisenone given
Environmental factors play an important role in AMD development.
“As in other complex diseases, environmental factors play an important role in AMD development.”
Quote in the paperSubstantial claim - Premisecitation
Diets high in antioxidants lutein and zeaxanthin and in omega-3 fatty acids have been linked to a decreased risk of neovascular AMD.
“Diets high in antioxidants lutein and zeaxanthin (found mostly in green leafy vegetables) and in omega-3 fatty acids (primarily found in fish) have been linked to a decreased risk of neovascular AMD (48, 134).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
The association of cardiovascular disease and its risk factors with AMD has not been consistently reproduced.
“The association of cardiovascular disease and its risk factors with AMD have not been consistently reproduced (26, 127, 136, 153).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation
Adaptive responses of the retina and RPE to aging are reflected in changes in expression of specific genes and cellular pathways.
“Adaptive responses of the retina and RPE to aging are reflected in changes in expression of specific genes and cellular pathways (171).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [171] Yoshida S, 2002, Investig. Ophthalmol. Vis. Sci.
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- Interpretationreasoning
Identification of a strong association between AMD and the CFH region prompted evaluation of genetic association between AMD and several other genes in the complement pathway.
“First, identification of a strong association between AMD and the CFH region prompted evaluation of genetic association between AMD and several other genes in the complement pathway.”
Quote in the paperSubstantial claim - Premisecitation
Except for two ABCA4 alleles, no variant in any other inherited macular dystrophy gene appears to show a significant association with AMD.
“Except for two ABCA4 alleles (6), no variant in any other inherited macular dystrophy gene appears to show a significant association with AMD (148).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisereasoning
The association between AMD and the CFH region has been validated in numerous studies worldwide.
“This breakthrough association has now been validated in numerous studies worldwide and has proven significant in several ways.”
Quote in the paperSubstantial claim - Premisecitation
Retinal expression profiles of senescence-accelerated mice highlighted expression changes for a different set of genes.
“Retinal expression profiles of senescence-accelerated mice highlighted expression changes for a different set of genes (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] source
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- Premisecitation
In AMD, several independent studies and a meta-analysis of multiple genome scans suggested susceptibility loci with large effect at chromosomes 1q31 and 10q26.
“In AMD, several independent studies, and a meta-analysis of multiple genome scans (47), suggested susceptibility loci with large effect at chromosomes 1q31 and 10q26.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] source
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- Premisecitation
The most significant breakthrough in understanding the genetics of AMD came in early 2005 with the identification of a strong association between disease and variants in and around the complement factor H (CFH) gene, which maps at 1q32 close to a linkage region at 1q25-31.
“Perhaps the most significant breakthrough in our understanding of the genetics of AMD came in early 2005 with the identification of a strong association between disease and variants in and around the complement factor H (CFH) gene (Figure 5); this gene maps at 1q32, close to a linkage region at 1q25–31 that was identified in several independent studies (see Figure 4).”
Quote in the paperSubstantial claim - Premisenone given
Linkage studies of AMD using large families have been difficult because of the late onset of disease, phenotypic variability, and phenocopy effects.
“Linkage studies of AMD using large families have been difficult because of the late onset of disease, phenotypic variability, and phenocopy effects.”
Quote in the paperSubstantial claim - Premisecitation
The contribution of genetics to AMD was documented throughout the 1990s with reports of familial aggregation, concordant phenotypes in twins, and a higher risk of disease in first-degree relatives of affected individuals.
“The contribution of genetics to AMD was carefully documented throughout the 1990s with reports of familial aggregation, concordant phenotypes in twins, and a higher risk of disease in first-degree relatives of affected individuals (69, 89, 91, 132).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation
Outside the complement pathway, the major genetic contributor to AMD susceptibility lies in the ARMS2/HTRA1 region.
“Outside the complement pathway, the major genetic contributor to AMD susceptibility lies in the ARMS2/HTRA1 region (see Figure 5).”
Quote in the paperSubstantial claim - Interpretationreasoning
In the absence of large, definitive, confirmatory studies, the possibility of publication bias in candidate gene association studies for AMD cannot be discounted.
“We caution that, in the absence of large, definitive, confirmatory studies, the possibility of publication bias cannot be discounted.”
Quote in the paperNot a substantial claim - Premisecitation
A gene C1QTNF5 mutated in patients with an autosomal dominant late-onset retinal/macular degeneration with sub-RPE deposits similar to AMD has also been examined.
“A gene (C1QTNF5) mutated in patients with an autosomal dominant late-onset retinal/macular degeneration with sub-RPE deposits similar to AMD has also been examined (68).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [68] source
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- Interpretationreasoning
Together, the complement pathway association signals account for a large part of the genetic contribution to AMD susceptibility.
“Together, these association signals account for a large part of the genetic contribution to AMD susceptibility.”
Quote in the paperSubstantial claim - Premisecitation
The association signal in the ARMS2/HTRA1 region was initially identified as a result of fine-mapping efforts designed to narrow the chromosome 10q26 linkage peak.
“The association signal in this region was initially identified as a result of fine-mapping efforts designed to narrow the chromosome 10q26 linkage peak (80, 122).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Typically, candidate genes for AMD have been selected based on a priori knowledge of the biological pathways involved in disease or on investigator prejudices about the pathways likely to contribute to disease susceptibility.
“Typically, these genes have been selected based on a priori knowledge of the biological pathways involved in disease or on investigator prejudices about the pathways likely to contribute to disease susceptibility (7, 149).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisereasoning
This fine-mapping analysis demonstrated that no single genetic variant could account for the contribution of the CFH locus to disease susceptibility.
“This analysis also demonstrated that no single genetic variant could account for the contribution of the CFH locus to disease susceptibility and was soon corroborated by others (e.g., 11, 107).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (e.g., 11, 107)
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- Premisecitation
Klein and colleagues were the first to report linkage to chromosome 1q25-31 in an apparently autosomal dominant pedigree with dry AMD.
“Klein and colleagues were the first to report linkage to chromosome 1q25–31 in an apparently autosomal dominant pedigree with dry AMD (92).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [92] source
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- Premisecitation
An initial comparison of young and aging human retinas identified differential expression of a small number of genes involved in stress and immune response, protein and energy metabolism, and inflammation.
“Nevertheless, an initial comparison of young and aging human retinas identified differential expression of a small number of genes involved in stress and immune response, protein and energy metabolism, and inflammation (171).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [171] Yoshida S, 2002, Investig. Ophthalmol. Vis. Sci.
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- Premisecitation
These linkage studies provided more modest evidence for linkage on many other chromosomes, including a region on chromosome 22 near TIMP3.
“In addition, these studies provided more modest evidence for linkage on many other chromosomes (2, 77, 104, 137, 160), including a region on chromosome 22 near TIMP3, the gene mutated in Sorsby fundus dystrophy (158) (Figure 4).”
Quote in the paperNot a substantial claim0 of 6 sources checked - Premisecitation
Other candidate gene studies focused on genes implicated in macular dystrophies with Mendelian inheritance and phenotypic similarities to AMD.
“Other candidate gene studies focused on genes implicated in macular dystrophies with Mendelian inheritance and phenotypic similarities to AMD (146).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [146] source
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- Premisecitation
Deletions in two genes near CFH, CFHR1 and CFHR3, have been associated with reduced risk of AMD.
“In addition to simple sequence changes, deletions in two genes near CFH, CFHR1 and CFHR3, have been associated with reduced risk of AMD (75, 143) (see Figure 5).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
The AMD-associated deletion-insertion polymorphism in ARMS2 is shown to mediate mRNA turnover.
“Equally significant, the AMD-associated deletion-insertion polymorphism in ARMS2 is shown to mediate mRNA turnover (52).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] source
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- Premisecitation
Other studies failed to replicate the SERPING1 association findings.
“however, other studies failed to replicate these findings (119).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [119] Park KH, 2009, Mol. Vis.
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- Interpretationreasoning
Gene profiles of aging retina and photoreceptors provide strong support for significant dysfunction in both energy and protein homeostasis.
“Gene profiles of aging retina and photoreceptors (described above) provide strong support for significant dysfunction in both energy and protein homeostasis.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Macula-specific immune responses are unlikely without specific initiators of the disease process.
“However, we believe that such macula-specific immune responses are unlikely without specific initiators of the disease process.”
Quote in the paperNot a substantial claim - Premisecitation
Photoreceptor outer-segment renewal is suggested to serve as a means to eliminate reactive oxygen species and other damaging molecules, minimizing resulting DNA damage.
“Photoreceptor outer-segment renewal is suggested to serve as a means to eliminate these reactive oxygen species and other damaging molecules, minimizing resulting DNA damage (164).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [164] source
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- Interpretationreasoning
Environmental factors including smoking, high-fat and antioxidant-deficient diet, chronic infection and/or inflammation may provide the final trigger(s) for AMD disease causation.
“Environmental factors, including smoking, high-fat and antioxidant-deficient diet, chronic infection and/or inflammation, may provide the final trigger(s) for disease causation.”
Quote in the paperNot a substantial claim - Premisecitation
A specific mitochondrial DNA polymorphism, A4917G, is reported to be associated with AMD.
“Consistent with the role of mitochondria in neurodegenerative disease, a specific mitochondrial DNA polymorphism, A4917G, is reported to be associated with AMD (20).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] source
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- Interpretationreasoning
A deficiency in antioxidant processes or increased oxidative stress could make photoreceptors and consequently RPE vulnerable to disease.
“A deficiency in antioxidant processes or increased oxidative stress could therefore make the photoreceptors and consequently RPE vulnerable to disease.”
Quote in the paperSubstantial claim - Interpretationreasoning
Genetic association studies failed to notice positive signals in candidate loci because they did not comprehensively evaluate genetic variants in the candidate locus.
“(c) did not comprehensively evaluate genetic variants in the candidate locus.”
Quote in the paperSubstantial claim - Interpretationreasoning
Genetic association studies failed to notice positive signals in candidate loci because they relied on relatively small sample sizes.
“(b) relied on relatively small sample sizes (GWASs typically examine thousands of individuals and are often better powered to detect modest association signals than previous studies);”
Quote in the paperSubstantial claim - Premisecitation
Aging-associated decline in chaperone networks and protein degradation systems can lead to protein aggregates that compromise biochemical functions and cellular health.
“aging-associated decline in these pathways can lead to protein aggregates that can compromise biochemical functions and cellular health (113, 124).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Even a slight decrease in the rate of clearing toxic protein and lipid debris could lead to their accumulation and even aggregation.
“Even a slight decrease in the rate of clearing toxic protein and lipid debris could lead to their accumulation and even aggregation.”
Quote in the paperSubstantial claim - Premisenone given
Genetic studies have established the roles of chronic inflammation and the complement pathway in AMD pathology.
“Genetic studies have established the roles of chronic inflammation and complement pathway in AMD pathology.”
Quote in the paperNot a substantial claim - Premisecitation
Variants in loci implicated in Mendelian disorders also contribute to susceptibility to more common forms of disease.
“There are now several examples where variants in loci implicated in Mendelian disorders also contribute to susceptibility to more common forms of disease; these include discoveries related to the genetics of blood lipid levels and coronary artery disease (83, 162), genetics of obesity (100, 163), and the genetics of height (96, 159).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Cumulative genetic load and exposure to environmental factors unique to each individual will produce variable age of onset and a range of AMD phenotypes.
“In this model, cumulative genetic load (i.e., net effect of different susceptibility or protective alleles) and exposure to environmental factors unique to each individual will produce variable age of onset and a range of AMD phenotypes.”
Quote in the paperNot a substantial claim - Premisecitation
Numerous studies have demonstrated a central role of mitochondria and energy homeostasis in the pathogenesis of aging-associated neurodegenerative diseases.
“Numerous studies have demonstrated a central role of mitochondria and energy homeostasis in the pathogenesis of aging-associated neurodegenerative diseases (98, 157, 166).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
A prospective population-based study identified an increased risk of developing AD in individuals with advanced AMD.
“Additionally, a prospective population-based study identified an increased risk of developing AD in individuals with advanced AMD (88).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [88] source
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- Premisecitation
Alzheimer's and Parkinson's are late-onset neurodegenerative diseases that share similarities with AMD.
“Alzheimer’s (AD) and Parkinson’s (PD) are late-onset neurodegenerative diseases (17) that share similarities with AMD.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] source
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- Premisecitation
The CEP-mouse model demonstrates the role of oxidative damage in inducing inflammation and eventually GA-like lesions.
“In addition, the CEP-mouse model demonstrates the role of oxidative damage in inducing inflammation and eventually GA-like lesions (72).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [72] source
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- Premisecitation
An association of impaired cognitive function with advanced AMD was reported in AREDS.
“An association of impaired cognitive function with advanced AMD was reported in AREDS (27).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] source
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- Interpretationreasoning
A clinically relevant AMD phenotype is identified only when a threshold effect is reached after combining susceptibility factors with stochastic contributions to risk.
“A clinically relevant phenotype is identified only when a threshold effect is reached after combining the susceptibility factors affecting each individual with stochastic contributions to risk (see Figures 3 and 6).”
Quote in the paperSubstantial claim - Interpretationreasoning
The RPE quickly becomes involved in AMD because of its close relationship with photoreceptors.
“we believe the RPE quickly becomes involved because of its close relationship with photoreceptors.”
Quote in the paperSubstantial claim - Interpretationreasoning
Genetic variants alter specific cellular functions or pathways in different cell types at early stages of life, but the functional consequences are not severe enough to produce a disease phenotype.
“We suggest that the genetic variants alter specific cellular function(s) or pathway(s) in different cell types (such as photoreceptors and RPE) at early stages of life but that the functional consequences are not severe enough to produce a disease phenotype.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Common variants that contribute to trait variation in loci known to harbor Mendelian variants were missed in several earlier studies.
“In all these instances, common variants that contribute to trait variation in loci known to harbor Mendelian variants were missed in several earlier studies.”
Quote in the paperSubstantial claim - Premisecitation
AREDS demonstrated that high doses of antioxidant vitamin C, vitamin E, beta-carotene, zinc, and copper are effective in slowing the progression of advanced stages of AMD by 25%.
“AREDS, a multicenter randomized and controlled clinical trial of oral supplements, demonstrated that high doses of antioxidant vitamin C, vitamin E, beta-carotene, zinc, and copper are effective in slowing the progression of advanced stages of AMD by 25% (4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] source
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- Premisecitation
Screening of potential functional candidate genes identified an association with an intronic variant within the SERPING1 gene.
“Screening of potential functional candidate genes identified association with an in-tronic variant within the SERPING1 gene (42);”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] source
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- Premisecitation
Mitochondrial dysfunction and oxidative stress, including mitochondrial DNA damage, have been implicated in AD, PD, and AMD.
“Mitochondrial dysfunction and oxidative stress, including mitochondrial DNA damage, have been implicated in all three diseases—AD, PD, and AMD (12, 17, 98, 165).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Multiple associations between AMD and HLA and cytokine genes have also been reported.
“Multiple associations between AMD and HLA and cytokine genes have also been reported (57, 58).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Screening of five fibulin genes for mutations associated with AMD revealed a variant in fibulin-5 in AMD patients.
“this screeening revealed a variant in fibulin-5 in AMD patients (145).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [145] source
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- Interpretationcitation
Accumulation and aggregation of toxic protein and lipid debris could cause RPE damage and release of chemokines and cytokines.
“This, in turn, could cause RPE damage and release of chemokines and cytokines (139).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [139] source
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- Premisecitation
Toxic amyloid oligomers have been demonstrated in drusen, basal deposits and RPE of human donor AMD eyes but not in control age-matched eyes without drusen.
“Toxic amyloid oligomers have been demonstrated in drusen, basal deposits and RPE of human donor AMD eyes but not in control age-matched eyes without drusen (102).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [102] source
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- Interpretationreasoning
Common and specific variants in complement and inflammatory response genes are likely to play critical roles in generating an array of AMD phenotypes.
“Common and specific variants in complement and inflammatory response genes are therefore likely to play critical roles in generating an array of AMD phenotypes.”
Quote in the paperSubstantial claim - Premisecitation
Differences in visual acuity score between ranibizumab-treated and control groups were considerable, with a mean increase of 7 letters in the treated group compared with a decrease of 10 letters in the placebo, sham-injected group (P < 0.001).
“Differences in visual acuity score in the treated and control groups were considerable, with a mean increase of 7 letters in the treated group compared with a decrease of 10 letters in the placebo, sham-injected group (P < 0.001) (144).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [144] source
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- Interpretationcitation
Compromised energy and protein metabolism in aging retinal photoreceptors and RPE likely constitute one of the early steps in AMD pathogenesis.
“Based on extensive biochemical, pathobiological, and genetic studies implicating oxidative stress and inflammation (12, 64, 165, 174), compromised energy and protein metabolism in aging retinal photoreceptors and RPE likely constitute one of the early steps in AMD pathogenesis (Figure 6).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Genetic association studies failed to notice positive signals in candidate loci because they defined the locus too narrowly.
“genetic association studies apparently failed to notice positive signals in these candidate loci because they (a) defined the locus too narrowly (e.g., by focusing only on coding regions and a short flanking promoter sequence, although it now appears that regulatory variants can be located 10s or 100s of kb away from the gene);”
Quote in the paperSubstantial claim - Premisecitation
Multiple associations between AMD and HLA and cytokine genes have been reported.
“Multiple associations between AMD and HLA and cytokine genes have also been reported (57, 58).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
The primary triggers of AMD may originate in the photoreceptors because of their high membrane and protein turnover and exposure to light and oxygen.
“Whereas the primary triggers of AMD may originate in the photoreceptors because of their high membrane and protein turnover and exposure to light and oxygen, we believe the RPE quickly becomes involved because of its close relationship with photoreceptors.”
Quote in the paperSubstantial claim - Interpretationreasoning
Differential immune response to aging-associated RPE damage leads to specific clinical manifestations of AMD.
“We suggest that differential immune response to aging-associated RPE damage (as elaborated in the preceding paragraph) leads to specific clinical manifestations.”
Quote in the paperSubstantial claim - Premisecitation
A preliminary analysis of interaction between CFH and ARMS2 susceptibility variants with AREDS-type dietary supplements suggests that oral supplementation with zinc was especially helpful for individuals with low-risk disease alleles at CFH.
“A preliminary analysis of interaction between CFH and ARMS2 susceptibility variants with the AREDS-type dietary supplements (90) suggests that oral supplementation with zinc was especially helpful for individuals with low-risk disease alleles at CFH.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [90] source
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- Premisecitation
A study of AREDS participants demonstrated that the presence of CFH polymorphisms and ARMS2-A69S independently contributed to progression to advanced AMD.
“A study of AREDS participants demonstrated that the presence of CFH polymorphisms and ARMS2-A69S independently contributed to progression to advanced AMD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [135] source
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- May combine two claims. 35
- Classified as probably not a substantial claim. 14
May combine two claims.
PremisecitationThe incidence of early AMD, large drusen and pigmentary changes in intermediate AMD, and choroidal neovascularization and geographic atrophy in advanced AMD increase with advancing age.
“The incidence of early AMD, large drusen and pigmentary changes in intermediate AMD, and choroidal neovascularization (CNV) and GA in advanced AMD increase with advancing age (51, 93).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPooled data from two population-based studies estimate the prevalence of advanced AMD at about 0.2% in ages 55 to 64, increasing to 13% in those older than 85 years.
“The pooled data from two population-based studies reveal an estimated prevalence of advanced AMD of ~0.2% in ages 55 to 64, increasing to 13% in those older than 85 years (140).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [140] source
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PremisecitationIn humans, advanced age is accompanied by increased vulnerability to disease, with progressive and generally irreversible loss of physiological functions; in the eye, these include deficits in visual processing and degenerative changes in retinal neurons and the RPE.
“In humans, advanced age is accompanied by increased vulnerability to disease, with progressive and generally irreversible loss of physiological functions; in the eye, these include deficits in visual processing and degenerative changes in retinal neurons (particularly rods and ganglion cells) and the RPE (16, 78).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationAdditional environmental factors that may influence AMD pathogenesis include sunlight exposure, alcohol use, and infection of bacterial pathogens, particularly Chlamydia pneumoniae.
“Additional environmental factors that may influence AMD pathogenesis include sunlight exposure (33, 35, 85), alcohol use (23, 24, 114), and infection of bacterial pathogens (particularly Chlamydia pneumoniae) (11, 76, 81).”
Quote in the paperNot a substantial claim0 of 9 sources checked- cites [33] Cruickshanks KJ, 2001, Arch. Ophthalmol.
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- cites [76] source
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- cites [81] source
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PremisecitationAlthough the RPE is the most affected cell layer in AMD, the photoreceptor layer is also severely attenuated.
“Although RPE is the most affected cell layer, the photoreceptor layer is also severely attenuated (87).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [87] source
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PremisecitationSmoking is a modifiable and consistently associated environmental factor, typically resulting in about two-fold increased risk of developing advanced AMD.
“Smoking is a modifiable and consistently associated environmental factor, typically resulting in about two-fold increased risk of developing advanced AMD (3, 112, 150, 155).”
Quote in the paperNot a substantial claim0 of 4 sources checkedMay combine two claims.
PremisecitationOlder individuals commonly have small drusen beneath the retina and cholesterol accumulation in Bruch's membrane.
“Older individuals commonly have small drusen beneath the retina and cholesterol accumulation in Bruch’s membrane (64, 74).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationA2E and mitochondrial dysfunction are reported to impair RPE phagocytosis and activate the complement system.
“A2E (a by-product of phototransduction, present in lipofuscin) and mitochondrial dysfunction are reported to impair RPE phagocytosis and activate the complement system (156, 178).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAging is a genetically regulated process defined by progressive decline of somatic cell functions with age.
“Aging is a genetically regulated process that is defined by progressive decline of somatic cell functions with age (46, 70).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe pathogenesis of Stargardt's disease is thought to result from the accumulation of A2E in the RPE.
“The pathogenesis of Stargardt’s disease, an early onset disorder whose symptoms resemble those of AMD, is thought to result from the accumulation of A2E in the RPE (110).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [110] source
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PremisecitationBasal linear deposits are composed primarily of membraneous material located external to the RPE basement membrane in Bruch's membrane and are believed to be more specific to AMD.
“basal linear deposits, which are composed primarily of membraneous material located external to the RPE basement membrane in Bruch’s membrane and are believed to be more specific to AMD (126).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [126] source
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May combine two claims.
PremisecitationIn choroidal neovascularization, vessels eventually break through the RPE, resulting in severe clinical phenotypes including neovascular AMD, hemorrhagic AMD, and disciform AMD.
“These vessels eventually break through the RPE (60), resulting in severe clinical phenotypes including (a) neovascular AMD, where lipid-rich fluid accumulates under the RPE and/or neural retina; (b) hemorrhagic AMD, where blood breaks through the RPE into the subretinal space; and (c) disciform AMD, where fibrous tissue with NV and altered RPE proliferates and replaces neural retina.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [60] source
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PremisecitationAnother sign of aging is the accumulation of lipofuscin, an undegradable fluorescent material; in the RPE, accumulation of lipofuscin may be due in large part to incomplete digestion of shed photoreceptor discs.
“Another sign of aging is the accumulation of lipofuscin, an undegradable fluorescent material; in the RPE, accumulation of lipofuscin may be due in large part to incomplete digestion of shed photoreceptor discs (142).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [142] source
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May combine two claims.
PremisecitationSoft drusen are associated with more extensive damage to the retina, RPE, and choroid, and predict more severe clinical outcomes such as geographic atrophy and choroidal neovascularization.
“Soft drusen are associated with more extensive damage to the retina, RPE, and choroid, and predict more severe clinical outcomes, such as GA and CNV (45).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn the Multi-ethnic Study of Atherosclerosis, the prevalence of AMD in persons aged 45 to 85 years was 2.4% in African-Americans, 4.2% in Hispanics, 4.6% in Chinese-descent individuals, and 5.4% in Caucasians.
“An analysis of U.S. participants in the Multi-ethnic Study of Atherosclerosis (MESA) showed the prevalence of AMD in persons aged 45 to 85 years to be 2.4% in African-Americans, 4.2% in Hispanics, 4.6% in Chinese-descent individuals, and 5.4% in Caucasians (94).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [94] source
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May combine two claims.
PremisecitationAging-associated expression changes in genes associated with mitochondrial function, protein metabolism, and immune response have been identified in several tissues and are consistent with some proposed mechanisms for late-onset neurodegenerative diseases.
“Aging-associated expression changes in genes associated with mitochondrial function, protein metabolism, and immune response have been identified in several tissues (173) and are consistent with some proposed mechanisms for late-onset neurodegenerative diseases (98, 113, 124, 166).”
Quote in the paperSubstantial claim0 of 5 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNeovascular AMD accounts for over 90% of severe central vision loss among patients with AMD.
“Neovascular AMD accounts for over 90% of severe central vision loss among patients with AMD (116, 154, 161).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChoroidal neovascularization refers to the growth of new blood vessels from the choroid through Bruch's membrane and under the RPE.
“CNV refers to the growth of new blood vessels from the choroid through Bruch’s membrane and under the RPE (125).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [125] source
Not checked in the free run.
May combine two claims.
PremisecitationGeographic atrophy shows abnormal RPE with cellular hypotrophy and hypertrophy, hypopigmentation and hyperpigmentation, loss of photoreceptors, Bruch's membrane thinning, and degeneration of the choriocapillaris.
“GA shows abnormal RPE with cellular hypotrophy and hypertrophy, hypopigmentation and hyperpigmentation, loss of photoreceptors, Bruch’s membrane thinning, and degeneration of the choriocapillaris (59, 103).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [59] Green WR, 1999, Mol. Vis.
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- cites [103] Lutty G, 1999, Mol. Vis.
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May combine two claims.
PremisecitationGenetic studies suggest modification of the susceptibility effect of ARMS2 by smoking, consistent with its involvement in mitochondrial function.
“Genetic studies also suggest modification of the susceptibility effect of ARMS2 by smoking (128), consistent with its involvement in mitochondrial function (66, 82).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationThe ARMS2 gene sequence is detected in primates and likely encodes a mitochondrial protein.
“The ARMS2 gene sequence is detected in primates and likely encodes a mitochondrial protein (82).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [82] source
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InterpretationreasoningLinkage studies have had only limited success in identifying complex disease susceptibility genes; nonetheless, in AMD they ultimately led to the discovery of genetic variants near CFH and ARMS2/HTRA1 as the strongest genetic contributors to AMD susceptibility.
“Overall, linkage studies have had only limited success in identifying complex disease susceptibility genes; nonetheless, in the case of AMD they ultimately led to the discovery of genetic variants near CFH and ARMS2/HTRA1 as the strongest genetic contributors to AMD susceptibility (see below).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenInitial reports of association with the CFH gene focused on the Y402H coding variant that alters a single amino acid residue in the CFH protein.
“Initial reports of association with the CFH gene focused on the Y402H coding variant that alters a single amino acid residue in the CFH protein.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationTwin studies demonstrated that genetic factors play a substantial role in the etiology of AMD, with some estimates suggesting that as much as 71% of the variation in the overall severity of AMD is genetically determined.
“Twin studies demonstrated that genetic factors play a substantial role in the etiology of AMD, with some estimates suggesting that as much as 71% of the variation in the overall severity of AMD is genetically determined (133).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [133] source
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May combine two claims.
PremisecitationSeveral additional complement genes have now been strongly associated with AMD, including complement 2 and/or complement factor B, complement 3, and complement factor I.
“These include complement 2 (C2) and/or complement factor B (CFB) (56), complement 3 (C3) (170), and complement factor I (CFI) (44).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationIndividually, APOE candidate gene studies have been relatively small and evidence for association has been modest, although together the published studies provide stronger evidence of an association between APOE and AMD.
“Individually, these studies have been relatively small, and evidence for association has been modest, although together the published studies provide stronger evidence of an association between APOE and AMD (10, 129, 177).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenBiological and functional studies of ARMS2 have been difficult because of the lack of a homologous gene in common model organisms such as mouse or zebra fish.
“Biological and functional studies of ARMS2 have been difficult because of the lack of a homologous gene in common model organisms (such as mouse or zebra fish).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationTwo reports implicated HTRA1 as a target of AMD susceptibility, whereas recent studies support the original claim of ARMS2 as a stronger candidate.
“Whereas two reports implicated HTRA1 as a target of AMD susceptibility (37, 167), recent studies support the original claim (122) of ARMS2 (previously LOC387715) as a stronger candidate (52, 82).”
Quote in the paperNot a substantial claim0 of 5 sources checkedMay combine two claims.
PremisecitationInitial reports of association between AMD and CFH included candidate gene approach, fine mapping of candidate loci, and the first successful whole-genome association study in humans, and were immediately replicated.
“Initial reports of association included candidate gene approach, fine mapping of candidate loci, and the first successful whole-genome association study in humans (40, 63, 65, 95) and were immediately replicated (175).”
Quote in the paperNot a substantial claim0 of 5 sources checkedMay combine two claims.
PremisereasoningAt least three potential candidate genes reside in the ARMS2/HTRA1 region of association; however, the identity of the gene that affects disease susceptibility is a subject of controversy.
“At least three potential candidate genes reside in the region of association; however, the identity of the gene that affects disease susceptibility is subject of controversy.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAn early attempt at fine mapping the CFH region showed that more than 20 variants in and around CFH were even more strongly associated with disease than the Y402H coding variant, potentially suggesting that regulation of expression of CFH and neighboring genes, rather than alterations in the coding sequence of CFH, mediates AMD susceptibility.
“An early attempt at fine mapping the region showed that >20 variants in and around CFH were even more strongly associated with disease than was the Y402H coding variant, potentially suggesting that regulation of the expression of CFH and neighboring genes, rather than alterations in the coding sequence of CFH, mediates AMD susceptibility (97).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [97] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisereasoningApolipoprotein E was an early target of candidate gene studies because of its presence in drusen, its key role in transport of lipids and cholesterol, and established association in Alzheimer's disease.
“Apolipoprotein E (APOE) was an early target of candidate gene studies because of its presence in drusen, its key role in transport of lipids and cholesterol, and established association in Alzheimer’s disease.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThis ARMS2/HTRA1 finding was later confirmed in several targeted studies and in a genome-wide association study.
“This finding was later confirmed in several targeted studies (107) and in a GWAS (37).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningIt is possible that susceptibility variants within the ARMS2 gene affect the activity of the HTRA1 promoter, so that both genes ARMS2 and HTRA1 influence AMD susceptibility.
“It is, nonetheless, possible that susceptibility variants within the ARMS2 gene affect the activity of HTRA1 promoter, which is only a few kilobases from ARMS2, so that both genes ARMS2 and HTRA1 influence AMD susceptibility.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningA multitude of candidate gene association studies have been carried out for AMD; their findings have not been replicated as widely or as strongly as those summarized above and should, for now, be treated as tentative.
“A multitude of candidate gene association studies have been carried out for AMD. Their findings, however, have not been replicated as widely or as strongly as those summarized above and should, for now, be treated as tentative.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAn association between the D299G TLR4 variant and AMD was initially reported but has not been validated.
“an association between the D299G TLR4 variant and AMD was initially reported (176) but has not been validated (36, 39).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationA polymorphism in the 5′-upstream region of ERCC6 has been associated with AMD susceptibility and was even suggested to exhibit epistatic interaction with CFH variants.
“A polymorphism in the 5′-upstream region of ERCC6, a gene implicated in DNA repair caused by oxidative stress and/or aging, has been associated with AMD susceptibility and was even suggested to exhibit epistatic interaction with CFH variants (152).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [152] source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
Interpretationnone givenA significant overlap in functional pathways highlighted by disparate research strategies is gradually emerging.
“A significant overlap in functional pathways highlighted by these disparate research strategies is gradually emerging.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationHomozygosity of the M280 allele in CX3CR1 showed defective cell migration and appeared to be associated with higher AMD susceptibility.
“homozygosity of the M280 allele showed defective cell migration and appeared to be associated with higher AMD susceptibility (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] source
Not checked in the free run.
May combine two claims.
InterpretationreasoningVariants in genes associated with a late-onset disease such as AMD are present since birth, implying that these are not sufficient for disease causation.
“Variants in genes associated with a late-onset disease (such as AMD) are present since birth, implying that these are not sufficient for disease causation.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMore recently, an association between AMD and Toll-like receptor 3 was reported, but this association was not replicated in other large cohorts.
“More recently, an association between AMD and another Toll-like receptor 3 (TLR3) was reported (168), but this association was not replicated in other large cohorts (41).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningProtective genetic haplotypes can reduce their impact on disease risk.
“Protective genetic haplo-types can reduce their impact on disease risk.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe resulting oxidative stress and protein misfolding are followed by lipid peroxidation and formation of protein aggregates, which may cause damage to outer-segment membrane biogenesis and RPE phagocytosis.
“The resulting oxidative stress and protein misfolding are followed by lipid peroxidation and formation of protein aggregates, which may cause damage to outer-segment membrane biogenesis and RPE phagocytosis.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Interpretationnone givenIn the multiple-hit model, each hit represents the addition of a genetic, environmental, or aging-related risk factor that increases disease susceptibility for each individual.
“Each hit represents the addition of a genetic, environmental, or aging-related risk factor that increases disease susceptibility for each individual.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationnone givenAging-associated changes may initiate the disease process and/or exacerbate the impact of genetic susceptibility variants.
“These changes may initiate the disease process and/or exacerbate the impact of genetic susceptibility variants.”
Quote in the paperNot a substantial claim- Rests on an assumption: Advanced age is the primary risk factor for AMD.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInheritance of the e4 allele of APOE is the only well-established genetic risk factor for sporadic AD.
“Inheritance of the e4 allele of APOE is the only well-established genetic risk factor for sporadic AD (147).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [147] source
Not checked in the free run.
The paper relies on this without support.
Late-onset diseases generally result from the interplay between multiple genetic susceptibility factors and environmental components.
“These late-onset diseases generally result from the interplay between multiple genetic susceptibility factors and environmental components.”
The paper relies on this without support.
Advanced age is the primary risk factor for AMD.
“Let us discuss the biological impact of advanced age, which is the primary risk factor for AMD.”
The paper relies on this without support.
Protein aggregates (lipofuscin and drusen) are hallmarks of retinal aging as well as of AMD.
“Notably, protein aggregates (lipofuscin and drusen) are hallmarks of retinal aging as well as of AMD.”
The paper relies on this without support.
AMD primarily affects the macula, a specialized region identified in the retina of primates, but not in other mammals or vertebrates.
“AMD primarily affects the macula, a specialized region identified in the retina of primates, but not in other mammals or vertebrates.”
The paper relies on this without support.
Control of modifiable risk factors such as smoking, hypertension, and elevated BMI may reduce the risk of developing AMD by as much as half.
“Control of modifiable risks factors such as smoking, hypertension, and elevated BMI may reduce the risk of developing AMD by as much as half.”
The paper relies on this without support.
Persons with bilateral large drusen and pigmentary changes have a 50% risk of progressing to advanced AMD in one eye over the next 5 years.
“For example, persons with bilateral large drusen and pigmentary changes have a 50% risk of progressing to advanced AMD in one eye over the next 5 years.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
AMD is a highly heritable progressive neurodegenerative disease that leads to loss of central vision through death of photoreceptors.
“AMD is a highly heritable progressive neurodegenerative disease that leads to loss of central vision through death of photoreceptors1,2.”
From Seven new loci associated with age-related macular degeneration (2013) · cites this paper as [1]
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The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice
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Sarks, J. P., Sarks, S. H., & Killingsworth, M. C. (1997) · Eye · doi:10.1038/eye.1997.137 · Cited by 140 · see citing works
Delcourt, C. (2001) · Archives of Ophthalmology · doi:10.1001/archopht.119.10.1463 · Cited by 140 · see citing works
Age-related macular degeneration and the immune response: implications for therapy
Nussenblatt, R. B., & Ferris, F. (2007) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2007.06.025 · Cited by 130 · see citing works
Age related macular degeneration and sun exposure, iris colour, and skin sensitivity to sunlight
Khan, J. C. (2006) · British Journal of Ophthalmology · doi:10.1136/bjo.2005.073825 · Cited by 121 · see citing works
Marmorstein, L. Y., McLaughlin, P. J., Peachey, N. S., Sasaki, T., & Marmorstein, A. D. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm199 · Cited by 119 · see citing works
Microarray analysis of gene expression in the aging human retina.
Yoshida, S., Yashar, B. M., Hiriyanna, S., & Swaroop, A. (2002) · PubMed · Cited by 114 · see citing works
Self-citationRetinal Dysfunction and Progressive Retinal Cell Death in SOD1-Deficient Mice
Hashizume, K., Hirasawa, M., Imamura, Y., Noda, S., Shimizu, T., Shinoda, K., Kurihara, T., Noda, K., Ozawa, Y., Ishida, S., et al. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.070730 · Cited by 114 · see citing works
Tuo, J., Ning, B., Bojanowski, C. M., Lin, Z.-N., Ross, R. J., Reed, G. F., Shen, D., Jiao, X., Zhou, M., Chew, E. Y., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603485103 · Cited by 114 · see citing works
Self-citationRhesus monkeys and humans share common susceptibility genes for age-related macular disease
Francis, P. J., Appukuttan, B., Simmons, E., Landauer, N., Stoddard, J., Hamon, S., Ott, J., Ferguson, B. M., Klein, M. L., Stout, J. T., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn167 · Cited by 114 · see citing works
Chong, E. W.-T., Kreis, A. J., Wong, T. Y., Simpson, J. A., & Guymer, R. H. (2008) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2007.12.005 · Cited by 112 · see citing works
Association of complement factor H polymorphisms with exudative age-related macular degeneration.
Chen, L. J., Liu, D. T. L., Tam, P. O. S., Chan, W. M., Liu, K., Chong, K. K. L., Lam, D. S. C., & Pang, C. P. (2006) · PubMed · Cited by 111 · see citing works
Lifespan and mitochondrial control of neurodegeneration
Wright, A. F., Jacobson, S. G., Cideciyan, A. V., Roman, A. J., Shu, X., Vlachantoni, D., McInnes, R. R., & Riemersma, R. A. (2004) · Nature Genetics · doi:10.1038/ng1448 · Cited by 111 · see citing works
Canter, J. A., Olson, L. M., Spencer, K., Schnetz-Boutaud, N., Anderson, B., Hauser, M. A., Schmidt, S., Postel, E. A., Agarwal, A., Pericak-Vance, M. A., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002091 · Cited by 110 · see citing works
Flood, V., Smith, W., Wang, J. J., Manzi, F., Webb, K., & Mitchell, P. (2002) · Ophthalmology · doi:10.1016/s0161-6420(02)01263-0 · Cited by 109 · see citing works
Proteasome Function and Protein Oxidation in the Aged Retina
Louie, J. L., Kapphahn, R. J., & Ferrington, D. A. (2002) · Experimental Eye Research · doi:10.1006/exer.2002.2022 · Cited by 106 · see citing works
Apolipoprotein (APOE) gene is associated with progression of age-related macular degeneration (AMD)
Baird, P. N., Richardson, A. J., Robman, L. D., Dimitrov, P. N., Tikellis, G., McCarty, C. A., & Guymer, R. H. (2006) · Human Mutation · doi:10.1002/humu.20288 · Cited by 105 · see citing works
Prospective Study of Alcohol Consumption and the Risk of Age-Related Macular Degeneration
Cho, E. (2000) · Archives of Ophthalmology · doi:10.1001/archopht.118.5.681 · Cited by 102 · see citing works
Control of Chemokine Gradients by the Retinal Pigment Epithelium
Shi, G., Maminishkis, A., Banzon, T., Jalickee, S., Li, R., Hammer, J., & Miller, S. S. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.08-1816 · Cited by 102 · see citing works
Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration
Spencer, K. L., Hauser, M. A., Olson, L. M., Schmidt, S., Scott, W. K., Gallins, P., Agarwal, A., Postel, E. A., Pericak-Vance, M. A., & Haines, J. L. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddm369 · Cited by 102 · see citing works
Ding, J., Lin, J. C., Mace, B. E., Herrmann, R., Sullivan, P. M., & Rickman, C. B. (2007) · Vision Research · doi:10.1016/j.visres.2007.07.025 · Cited by 97 · see citing works
Visual cells, daily rhythms, and vision research
Young, R. W. (1978) · Vision Research · doi:10.1016/0042-6989(78)90205-5 · Cited by 91 · see citing works
Baird, P. N., Robman, L. D., Richardson, A. J., Dimitrov, P. N., Tikellis, G., McCarty, C. A., & Guymer, R. H. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn018 · Cited by 90 · see citing works
Bonnel, S., Mohand-Said, S., & Sahel, J.-A. (2003) · Experimental Gerontology · doi:10.1016/s0531-5565(03)00093-7 · Cited by 89 · cited 2× · see citing works
“In humans, advanced age is accompanied by increased vulnerability to disease, with progressive and generally irreversible loss of physiological functions; in the eye, these include deficits in visual processing and degenerative changes in retinal neurons (particularly rods and ganglion cells) and the RPE (16, 78).”
Toll-like receptor polymorphisms and age-related macular degeneration
Edwards, A. O., Chen, D., Fridley, B. L., James, K. M., Wu, Y., Abecasis, G., Swaroop, A., Othman, M., Branham, K., Iyengar, S. K., et al. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.07-1378 · Cited by 84 · see citing works
Self-citationSerological Association Between Chlamydia pneumoniae Infection and Age-Related Macular Degeneration
Kalayoglu, M. V. (2003) · Archives of Ophthalmology · doi:10.1001/archopht.121.4.478 · Cited by 82 · cited 1× · see citing works
“Additional environmental factors that may influence AMD pathogenesis include sunlight exposure (33, 35, 85), alcohol use (23, 24, 114), and infection of bacterial pathogens (particularly Chlamydia pneumoniae) (11, 76, 81).”
Molecular genetics of age-related macular degeneration
Stone, E. M. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.20.2285 · Cited by 79 · see citing works
Schaumberg, D. A. (2007) · Archives of Ophthalmology · doi:10.1001/archopht.125.3.300 · Cited by 79 · see citing works
Interleukin-8 promoter polymorphism -251A/T is a risk factor for age-related macular degeneration
Goverdhan, S. V., Ennis, S., Hannan, S. R., Madhusudhana, K. C., Cree, A. J., Luff, A. J., & Lotery, A. J. (2008) · British Journal of Ophthalmology · doi:10.1136/bjo.2007.123190 · Cited by 79 · see citing works
Association of HLA Class I and Class II Polymorphisms with Age-Related Macular Degeneration
Goverdhan, S. V., Howell, M. W., Mullins, R. F., Osmond, C., Hodgkins, P. R., Self, J., Avery, K., & Lotery, A. J. (2005) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.04-0928 · Cited by 78 · see citing works
Gupta, S., Murthy, G. V. S., Morrison, N., Price, G. M., Dherani, M., John, N., FLETCHER, A. E., & Chakravarthy, U. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.06-0712 · Cited by 75 · see citing works
Kaur, I., Katta, S., Hussain, A., Hussain, N., Mathai, A., Narayanan, R., Hussain, A., Reddy, R. K., Majji, A. B., Das, T., et al. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-0560 · Cited by 68 · see citing works
Mechanisms of aging in senescence-accelerated mice
Carter, T. A., Greenhall, J. A., Yoshida, S., Fuchs, S., Helton, R., Swaroop, A., Lockhart, D. J., & Barlow, C. (2005) · Genome Biology · doi:10.1186/gb-2005-6-6-r48 · Cited by 64 · see citing works
Self-citationFuse, N., Miyazawa, A., Mengkegale, M. G., et al. (2006) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2006.07.030 · Cited by 63 · see citing works
Despriet, D. D. G., Bergen, A. A. B., Merriam, J. E., Zernant, J., Barile, G. R., Smith, R. T., Barbazetto, I. A., van Soest, S., Bakker, A., de Jong, P. T. V. M., et al. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.07-0656 · Cited by 60 · see citing works
Winkler, B. S. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.08-1785 · Cited by 50 · see citing works
Alcohol consumption and the 5-year incidence of age-related maculopathy
Moss, S. E., Klein, R., Klein, B. E. K., Jensen, S. C., & Meuer, S. M. (1998) · Ophthalmology · doi:10.1016/s0161-6420(98)95016-3 · Cited by 49 · see citing works
Is Chlamydia pneumoniae infection a risk factor for age related macular degeneration?
Ishida, O. (2003) · British Journal of Ophthalmology · doi:10.1136/bjo.87.5.523 · Cited by 48 · see citing works
Gene expression variation in the adult human retina
Chowers, I., Liu, D., Farkas, R. H., Gunatilaka, T. L., Hackam, A. S., Bernstein, S. L., Campochiaro, P. A., Parmigiani, G., & Zack, D. J. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg326 · Cited by 48 · see citing works
Huang, J.-D., Curcio, C. A., & Johnson, M. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.07-1196 · Cited by 47 · see citing works
The challenge of modeling macular degeneration in mice
Marmorstein, A. D., & Marmorstein, L. Y. (2007) · Trends in Genetics · doi:10.1016/j.tig.2007.03.001 · Cited by 44 · see citing works
Park, K. H., Ryu, E., Tosakulwong, N., Wu, Y., & Edwards, A. O. (2009) · PubMed Central · Cited by 40 · see citing works
Geographic atrophy in age-related macular degeneration and TLR3.
Edwards, A. O., Swaroop, A., & Seddon, J. M. (2009) · PubMed · Cited by 18 · see citing works
Self-citationBringing the genetics of macular degeneration into focus
Haines, J. L., Spencer, K. M., & Pericak-Vance, M. A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708151104 · Cited by 15 · see citing works
Risk Factors for Age-Related Maculopathy: The Visual Impairment Project
McCarty, C. A. (2001) · Archives of Ophthalmology · doi:10.1001/archopht.119.10.1455 · Cited by 12 · see citing works
Is age-related maculopathy associated with Alzheimers disease?
Klaver, C. C. W., Ott, A., Hofman, A., et al. (1998) · Cited by 9 · see citing works
Edwards, K. M., & Modjarrad, K. (2009) · New England Journal of Medicine · doi:10.1056/nejmbkrev0809168 · Cited by 5 · see citing works
Flagged first, then by citations
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Cited by
Sorted by citations
Seven new loci associated with age-related macular degeneration
The AMD Gene Consortium (2013) · Nature Genetics · doi:10.1038/ng.2578 · Cited by 788 · see citing works
Chen, W., Stambolian, D., Edwards, A. O., Branham, K. E., Othman, M., Jakobsdottir, J., Tosakulwong, N., Pericak-Vance, M. A., Campochiaro, P. A., Klein, M. L., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912702107 · Cited by 506 · see citing works
Self-citationThe Blood-Retina Barrier: Tight Junctions and Barrier Modulation
Campbell, M., & Humphries, P. (2013) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4614-4711-5_3 · Cited by 270 · see citing works
Transcriptome analysis and molecular signature of human retinal pigment epithelium
Strunnikova, N. V., Maminishkis, A., Barb, J. J., Wang, F., Zhi, C., Sergeev, Y., Chen, W., Edwards, A. O., Stambolian, D., Abecasis, G., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq129 · Cited by 269 · see citing works
Self-citationCRX ChIP-seq reveals the <i>cis</i>-regulatory architecture of mouse photoreceptors
Corbo, J. C., Lawrence, K. A., Karlstetter, M., Myers, C. A., Abdelaziz, M., Dirkes, W., Weigelt, K., Seifert, M., Benes, V., Fritsche, L. G., et al. (2010) · Genome Research · doi:10.1101/gr.109405.110 · Cited by 219 · see citing works
Scholz, R., Sobotka, M., Caramoy, A., Stempfl, T., Moehle, C., & Langmann, T. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0431-4 · Cited by 177 · see citing works
Hypomethylation of the IL17RC Promoter Associates with Age-Related Macular Degeneration
Wei, L., Liu, B., Tuo, J., Shen, D., Chen, P., Li, Z., Liu, X., Ni, J., Dagur, P., Sen, H. N., et al. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.10.013 · Cited by 167 · see citing works
Self-citationGenetic association with response to intravitreal ranibizumab in patients with neovascular AMD
Kloeckener-Gruissem, B., Barthelmes, D., Labs, S., Schindler, C., Kurz-Levin, M., Michels, S., Fleischhauer, J., Berger, W., Sutter, F., & Menghini, M. (2011) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.10-6080 · Cited by 120 · see citing works
Scholz, R., Caramoy, A., Bhuckory, M. B., Rashid, K., Chen, M., Xu, H., Grimm, C., & Langmann, T. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0422-5 · Cited by 111 · see citing works
Genetics of age-related macular degeneration: current concepts, future directions
DeAngelis, M. M., Silveira, A. C., Carr, E. A., & Kim, I. K. (2011) · Seminars in Ophthalmology · doi:10.3109/08820538.2011.577129 · Cited by 94 · see citing works
Age-related macular degeneration: The importance of family history as a risk factor
Shahid, H., Khan, J. C., Cipriani, V., Sepp, T., Matharu, B. K., Bunce, C., Harding, S. P., Clayton, D. G., Moore, A. T., Yates, J. R. W., et al. (2012) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2011-300193 · Cited by 84 · see citing works
A2E accumulation influences retinal microglial activation and complement regulation
Ma, W., Coon, S., Zhao, L., Fariss, R. N., & Wong, W. T. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.06.010 · Cited by 92 · see citing works
Retinal prostheses: progress toward the next generation implants
Ghezzi, D. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00290 · Cited by 83 · see citing works
Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration
Molday, R. S., & Zhang, K. (2010) · Progress in Lipid Research · doi:10.1016/j.plipres.2010.07.002 · Cited by 82 · see citing works
Kim, S.-Y., Yang, H.-J., Chang, Y.-S., Kim, J.-W., Brooks, M., Chew, E. Y., Wong, W. T., Fariss, R. N., Rachel, R. A., Cogliati, T., et al. (2014) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.14-15091 · Cited by 72 · see citing works
Self-citationWavre-Shapton, S. T., Tolmachova, T., da Silva, M. L., Futter, C. E., & Seabra, M. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057769 · Cited by 67 · see citing works
Seo, S.-J., Krebs, M. P., Mao, H., Jones, K., Conners, M., & Lewin, A. S. (2012) · Experimental Eye Research · doi:10.1016/j.exer.2012.05.013 · Cited by 51 · see citing works
Posttranslational Modifications of the Photoreceptor-Specific ABC Transporter ABCA4
Tsybovsky, Y., Wang, B., Quazi, F., Molday, R. S., & Palczewski, K. (2011) · Biochemistry · doi:10.1021/bi200774w · Cited by 39 · see citing works
Guymer, R. H., Silva, R., Ghadessi, M., Leal, S., Gashaw, I., Damask, A., Paulding, C., & Rittenhouse, K. D. (2024) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.65.8.17 · Cited by 6 · see citing works
- Authors
- Swaroop, A., Chew, E. Y., Bowes Rickman, C., & Abecasis, G. R.
- Affiliations
- National Institutes of Health (US)
- Departments of Ophthalmology and Cell Biology, Duke University Medical Center, Durham, North Carolina, 27710
- University of Michigan (US)
- Venue
- Annual Review of Genomics and Human Genetics
- Publisher
- Annual Reviews
- Published
- 2009-09-01
- Volume
- 10
- Issue
- 1
- Pages
- 19-43
- ISSN
- 1527-8204 (ISSN-L)
- 1545-293X
- PMC
- PMC3469316
- OpenAlex
- W2122414444
- Semantic Scholar
- 748e3a534e9028c68bb07506fac788787ee2073d
- Cited by
- 270
- References
- 184
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 10 · 2023: 6 · 2022: 14 · 2021: 8 · 2020: 16 · 2019: 10 · 2018: 10 · 2017: 14 · 2016: 11 · 2015: 25 · 2014: 28 · 2013: 32 · 2012: 22
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annual Review of Genomics and Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 EY999999)
- National Eye Institute (ZIAEY000473, ZIAEY000475, R01EY016862)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- age-related macular degeneration, genetic susceptibility, late-onset disease, aging, neurodegenerative diseases, AMD pathogenesis, gene pathways, disease mechanisms, complex diseases
- MeSH terms
- Animals, Disease Models, Animal, Eye, Humans, Life Style, Macular Degeneration, Age of Onset, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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