Atrophic Macular Degeneration
Introduction
Section titled “Introduction”Atrophic macular degeneration, commonly referred to as geographic atrophy (GA), represents a late-stage manifestation of age-related macular degeneration (AMD). AMD is recognized as the leading cause of irreversible blindness among the elderly across many countries. .
The statistical power of studies, particularly for detecting subtle or subtype-specific genetic effects, can also be a constraint. Insufficient power in replication cohorts has been cited as a reason for the inability to consistently confirm novel genetic associations observed in discovery cohorts. [1]Even for previously identified loci, some variants might show small to modest effect size differences between AMD subtypes, such as those in theC2 and TIMP3 loci, which may not reach statistical significance despite larger datasets. [1] This decreased power can also lead to a generalized decrease in significance (higher P-values) when specific mixed-phenotype cases are excluded to enhance purity, as seen when 25% of the CNV cases were removed from an analysis. [1]
Ancestry-Specific Findings and Generalizability
Section titled “Ancestry-Specific Findings and Generalizability”A significant limitation of many genetic studies on macular degeneration is their predominant focus on populations of European ancestry.[1] This narrow demographic focus restricts the generalizability of findings to other ethnic groups and may overlook unique genetic architectures. Studies indicate that populations of Asian ancestry, for example, exhibit distinct clinical presentations of AMD, including conditions like polypoidal choroidal vasculopathy which accounts for a substantial proportion of exudative AMD in these groups, and potentially different responses to treatments. [2] Consequently, it remains uncertain whether the underlying genetic characteristics influencing AMD susceptibility and progression are similar or different between European and Asian ancestries, highlighting a critical knowledge gap and the need for more diverse research cohorts. [2]
Untapped Genetic and Environmental Contributions
Section titled “Untapped Genetic and Environmental Contributions”Current genome-wide association studies (GWAS) may not fully capture the entirety of genetic risk factors for macular degeneration. A notable limitation is the limited coverage of low-frequency coding variants, which can have significant functional impacts and often exhibit ethnic-specific patterns.[2]These less common variants, including those with minor allele frequencies between 0.05 and 0.10, might possess stronger effects for subjects with moderate or high baseline disease severity and may not have been identified by previous case-control studies.[3]Moreover, while some studies account for major environmental confounders like smoking history and age, the complex interplay between numerous other environmental factors and genetic predispositions (gene-environment interactions) often remains largely unexplored, contributing to the phenomenon of “missing heritability” where the total genetic contribution to the disease is not fully explained by identified variants.[4]
Variants
Section titled “Variants”Variants within genes of the complement system, lipid metabolism, and other pathways are significantly associated with the risk and progression of atrophic macular degeneration. These genetic variations can alter protein function or expression, contributing to the retinal inflammation, lipid accumulation, and cellular dysfunction characteristic of the disease.
The complement system plays a critical role in the immune response, and dysregulation of this system is a major factor in atrophic macular degeneration.CFH(Complement Factor H) is a crucial regulator that prevents uncontrolled complement activation, and variants within this gene are strongly linked to an increased risk of atrophic macular degeneration.[5] For instance, the rs1061170 variant is a widely recognized susceptibility locus for AMD. [6] The CFHR gene family, including CFHR1 through CFHR4, also encodes proteins that regulate the complement cascade. Several CFHR genes, such as CFHR2, CFHR3, CFHR4, and CFHR5, have shown associations with AMD, which may be due to their close proximity and shared regulatory mechanisms with CFH. [7] The variant rs61818925 , located within the CFHR1-CFHR4 region, likely contributes to AMD risk by influencing this complex complement regulation. [7] Another key gene, C3 (Complement Component 3), is central to all complement pathways, and variants in C3 are also linked to AMD. [7] The rs2230199 variant in C3has demonstrated a significant association with early forms of AMD, suggesting its involvement in the disease’s initiation or progression.[8]
ARMS2 (Age-Related Maculopathy Susceptibility 2) represents another major genetic risk factor for AMD, located on chromosome 10q26. [7] The rs10490924 variant in ARMS2is a particularly strong genetic determinant of AMD risk, especially for advanced forms of the disease.[6] This variant leads to a non-synonymous change (A69S) in the ARMS2 protein, implying a direct alteration of its function that contributes to retinal pathology, possibly by affecting mitochondrial function or extracellular matrix integrity. [9] APOE(Apolipoprotein E) is a protein vital for lipid transport and metabolism, with significant roles in lipid homeostasis within the retina.[6] The rs429358 variant in APOE, also known as the ε4 allele, has been consistently associated with AMD, suggesting that altered lipid processing and inflammation play a role in the accumulation of drusen, a hallmark of atrophic AMD. [6]
Other genes also contribute to the genetic architecture of AMD. SKIC2, also known as SKIV2L(Superkiller viralicase 2-like), encodes an RNA helicase involved in cellular RNA metabolism and has been identified as a protective factor for age-related macular degeneration.[10] While the specific impact of the rs116503776 variant requires further investigation, variations in this gene may enhance cellular resilience and contribute to protection against retinal degeneration.[10] CETP(Cholesteryl Ester Transfer Protein) is critical in cholesterol metabolism, particularly in regulating high-density lipoprotein (HDL) levels.[8] Variants within CETP, including rs5817082 , have demonstrated associations with advanced AMD, highlighting the importance of lipid metabolism pathways in the disease.[8] Dysregulation of cholesterol and lipid processing, influenced by these genetic variations, can lead to the accumulation of drusen in the retina, thereby accelerating AMD progression. [8]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs61818925 | CFHR1 - CFHR4 | atrophic macular degeneration |
| rs116503776 | SKIC2 | age-related macular degeneration, disease progression measurement atrophic macular degeneration age-related macular degeneration |
| rs187328863 | KCNT2 | atrophic macular degeneration |
| rs2230199 rs147859257 | C3 | age-related macular degeneration wet macular degeneration atrophic macular degeneration age-related macular degeneration, disease progression measurement blood protein amount |
| rs1061170 rs35292876 rs121913059 | CFH | age-related macular degeneration wet macular degeneration atrophic macular degeneration membrane-associated progesterone receptor component 2 measurement complement factor H measurement, protein binding measurement |
| rs10490924 rs3750846 | ARMS2 | age-related macular degeneration wet macular degeneration atrophic macular degeneration age-related macular degeneration, wet macular degeneration refractive error |
| rs429358 | APOE | cerebral amyloid deposition measurement Lewy body dementia, Lewy body dementia measurement high density lipoprotein cholesterol measurement platelet count neuroimaging measurement |
| rs148553336 | KCNT2 - CFH | atrophic macular degeneration |
| rs5754227 | SYN3 | atrophic macular degeneration body surface area age-related macular degeneration, COVID-19 sexual dimorphism measurement |
| rs5817082 | CETP | atrophic macular degeneration metabolic syndrome age-related macular degeneration high density lipoprotein cholesterol measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Defining Atrophic Macular Degeneration and its Stages
Section titled “Defining Atrophic Macular Degeneration and its Stages”Atrophic macular degeneration is a prominent cause of irreversible vision loss among the elderly, commonly referred to as “dry age-related macular degeneration” (AMD) or “nonneovascular age-related macular degeneration”.[8] This condition is characterized by a gradual deterioration of the macula, the central part of the retina responsible for sharp, detailed vision. The earliest identifiable features include abnormalities in the retinal pigment epithelium (RPE) and the accumulation of extracellular deposits known as drusen, which are situated between Bruch’s membrane and the RPE. [8]
The progression of atrophic macular degeneration involves a series of morphological changes that are crucial for its conceptual understanding and operational definition. Early stages are often marked by the presence of soft drusen, defined as larger than 0.63 mm, or the onset of RPE depigmentation.[8]As the disease advances, these drusen may exceed 0.125 mm in diameter and can be either soft distinct or soft indistinct, sometimes appearing alongside areas of increased retinal pigment or further depigmentation.[8] The ultimate and most severe form of atrophic AMD is geographic atrophy (GA), characterized by clearly demarcated areas of RPE and photoreceptor cell loss, leading to significant central vision impairment. [8]
Classification Systems and Severity Grading
Section titled “Classification Systems and Severity Grading”The classification of atrophic macular degeneration relies on structured systems to standardize diagnosis, research, and clinical management. A foundational framework is the “International Classification and Grading System for Age-Related Maculopathy and Age-Related Macular Degeneration,” which provides a comprehensive nosology for the spectrum of AMD.[11]Within this and other systems, severity is graded based on the size and type of drusen, the area they cover, and the presence of pigmentary abnormalities.[12]
Several specific classification scales are utilized in clinical and research settings to categorize the disease, including the “Three Continent Consortium (3CC) Severity Scale,” which distinguishes between mild, moderate, and severe early AMD stages.[12] Other widely applied systems include the AREDS-9 step classification scheme, the Rotterdam Eye Study classification, and the Beckman Clinical Classification. [12]For advanced atrophic disease, the “Clinical Age-Related Maculopathy Grading System (CARMS)” precisely defines GA, with Grade 4 encompassing GA that involves the macular center or noncentral GA measuring at least 350 µm in size.[1] While CARMS Grade 5 primarily describes exudative (wet) AMD, cases presenting with both GA and choroidal neovascularization (CNV) in the same eye are classified under Grade 5 (CNV), highlighting the distinct yet sometimes co-occurring advanced phenotypes. [1]
Key Terminology and Diagnostic Approaches
Section titled “Key Terminology and Diagnostic Approaches”The precise terminology used in atrophic macular degeneration is critical for consistent clinical and research communication. Beyond the main disease label, “drusen” are key terms, with distinctions made between hard drusen (small, often innocuous deposits that may be present in unaffected individuals) and soft drusen (larger, often indistinct deposits indicative of early AMD).[8]“Retinal pigment epithelium (RPE) depigmentation” and “increased retinal pigment” are also significant terms describing changes in the RPE layer, which are crucial diagnostic markers for disease onset and progression.[8] These terms are integral to both clinical and research criteria for defining the presence and stage of atrophic AMD.
The primary method for diagnosing and monitoring atrophic macular degeneration involves detailed ophthalmic examination, fundamentally relying on color fundus photography.[12] Multimodal imaging, which combines various advanced imaging techniques, has become an important approach for comprehensive evaluation of nonneovascular AMD, including its dry forms. [13] Optical coherence tomography (OCT), for instance, provides high-resolution cross-sectional images of the retina, allowing for precise measurement of retinal and choroidal thickness and detailed visualization of drusen and RPE abnormalities, supporting accurate diagnostic and measurement criteria. [14]Specific thresholds, such as soft drusen exceeding 0.63 mm or GA lesions measuring at least 350 µm, serve as established cut-off values for classifying disease stages.[8]
Signs and Symptoms
Section titled “Signs and Symptoms”Early Clinical Manifestations and Progression Markers
Section titled “Early Clinical Manifestations and Progression Markers”Atrophic macular degeneration, often referred to as dry age-related macular degeneration (AMD), typically manifests with a gradual onset of visual symptoms, or may be asymptomatic in its initial stages. Common subjective symptoms, when present, can include blurred central vision, difficulty reading or performing other detailed tasks, and problems adapting to changes in lighting.[15]The disease is a leading cause of irreversible blindness in the elderly, highlighting the diagnostic significance of early detection and monitoring of these symptoms.
Clinically, early atrophic macular degeneration is characterized by observable abnormalities in the retinal pigment epithelium (RPE) and the deposition of drusen, which are extracellular deposits, between Bruch’s membrane and the RPE.[8]The presence of large soft drusen, defined as over 125 µm in diameter, with either distinct or indistinct borders, and reticular drusen are considered strong indicators of an increased risk for progression to more advanced, vision-impairing forms of the disease.[8]Additionally, areas of RPE depigmentation (decreased pigment) or increased pigment are also key clinical signs associated with disease progression.[8]
Objective Assessment and Imaging Biomarkers
Section titled “Objective Assessment and Imaging Biomarkers”The diagnosis and monitoring of atrophic macular degeneration rely on a suite of objective assessment methods to characterize its clinical presentation and progression. Fundus photography is a foundational diagnostic tool used to visualize and document drusen, pigmentary changes, and ascertain the presence of early AMD[12]. [6] Optical Coherence Tomography (OCT) provides detailed cross-sectional images of the retina, allowing for the measurement of retinal and choroidal thickness and the detection of subtle structural changes in the macula [16]. [14] Multimodal imaging, which may include autofluorescence imaging, helps evaluate the health and integrity of the RPE and identify areas of geographic atrophy. [6], [13]Several standardized classification systems are utilized to grade the severity and distinct clinical phenotypes of age-related macular degeneration, including those that lead to the atrophic form. These include the International Classification and Grading System for Age-Related Maculopathy and Macular Degeneration[6], [11]and the Three Continent Consortium (3CC) Severity Scale, which categorizes early AMD into mild, moderate, and severe stages based on drusen characteristics and pigmentary abnormalities [12]. [17]Other frameworks, such as the AREDS-9 step classification scheme, also provide detailed criteria for staging the disease based on the extent of drusen and RPE changes, serving as important prognostic indicators for disease advancement[12]
Phenotypic Diversity and Severity Spectrum
Section titled “Phenotypic Diversity and Severity Spectrum”Atrophic macular degeneration presents with significant phenotypic diversity and inter-individual variability, influenced by factors such as age and potentially genetic predispositions. Early AMD encompasses various phenotypes characterized by soft drusen, RPE depigmentation, or a combination of drusen with areas of increased pigment.[8] These early stages may progress to late AMD, which includes the atrophic form, specifically known as geographic atrophy (GA), and exudative (wet) AMD [8]. [1] Geographic atrophy is a distinct, vision-impairing clinical phenotype marked by well-demarcated areas of atrophy affecting the RPE and overlying photoreceptors. [8]
The severity of atrophic macular degeneration is classified based on objective findings such as the size and area of drusen, as well as the presence and extent of pigmentary abnormalities.[12]For instance, the Clinical Age-Related Maculopathy Grading System (CARMS) defines Grade 4 as geographic atrophy involving the macular center or noncentral GA measuring at least 350 µm in size.[1]The identification of large soft drusen and RPE abnormalities carries significant diagnostic value, acting as red flags and prognostic indicators for progression to advanced atrophic disease and potential irreversible vision loss. A thorough differential diagnosis is crucial to distinguish atrophic AMD from other causes of visual impairment, such as retino-choroidal inflammatory diseases or diabetic retinopathy.[6]
Causes
Section titled “Causes”Atrophic macular degeneration, often referred to as dry AMD, is a complex condition influenced by a combination of genetic predispositions, environmental factors, and intricate interactions between them. The development and progression of this late-onset multifactorial disease involve cumulative effects over a lifetime, leading to the degeneration of macular tissue and vision loss.[18]
Genetic Predisposition to Atrophic Macular Degeneration
Section titled “Genetic Predisposition to Atrophic Macular Degeneration”Genetic factors play a significant role in determining an individual’s susceptibility to atrophic macular degeneration. Twin studies have provided evidence for a strong genetic influence on early age-related maculopathy.[19]Genome-wide association studies (GWAS) have identified numerous genetic variants and loci associated with the disease, underscoring its polygenic nature[2], [6], [8], [12], [14], [20], [21], [22]. [23] Key genetic contributions include variants near TIMP3and high-density lipoprotein-associated loci, which influence susceptibility.[20] The CFH(Complement Factor H) gene is a well-established risk factor, with specific variants increasing the risk of atrophic macular degeneration.[5] Additionally, the ARMS2/HTRA1 locus is known to confer differential susceptibility to advanced subtypes of the condition [24]. [1] Other identified genetic regions include TNXB-FKBPL-NOTCH4 on chromosome 6p21.3, as well as novel loci such as TRPM1 and ABHD2/RLBP1 [6]. [23] Variants in genes like RDH5 and SLC6A20have also been associated with changes in macular thickness, indicating their role in retinal structure and function related to the disease.[14]
Environmental and Lifestyle Risk Factors
Section titled “Environmental and Lifestyle Risk Factors”Beyond genetics, several environmental and lifestyle factors contribute to the risk of developing atrophic macular degeneration. Smoking is a particularly significant and well-documented modifiable risk factor[6]. [25] Various studies investigating the prevalence and associated risk factors across different populations, such as elderly Chinese and Korean populations, consistently highlight the role of environmental influences [20]. [26]While specific dietary factors are not detailed in the provided context, the general assessment of “lifestyle data” in research implies broader habits contribute.[6]The presence of systemic comorbidities has also been identified through genome-wide association studies in diverse populations, suggesting that other health conditions can indirectly affect the development of atrophic macular degeneration.[22]
Complex Interactions and Age-Related Changes
Section titled “Complex Interactions and Age-Related Changes”The development of atrophic macular degeneration is further complicated by interactions between genetic predispositions and environmental triggers, as well as the pervasive influence of age. Research has explicitly explored gene-environment interactions, revealing how genetic variants can modify the impact of environmental exposures.[9] For instance, specific variants in the CFHgene, when combined with smoking, demonstrate a gene-environment interaction that influences the progression of atrophic macular degeneration.[27]Interactions between single nucleotide polymorphisms in theNOS2A gene and smoking have also been analyzed, further illustrating these complex relationships. [28]As implied by its name, age-related macular degeneration primarily manifests with advancing age, making it the most significant non-modifiable risk factor.[29]With aging, anatomical changes such as those observed in Bruch’s membrane and the accumulation of choroidal macrophages contribute to the pathophysiology of early and advanced atrophic macular degeneration.[30]
Biological Background
Section titled “Biological Background”Pathological Progression and Retinal Degeneration
Section titled “Pathological Progression and Retinal Degeneration”Atrophic macular degeneration, also known as geographic atrophy, is a chronic, progressive eye condition characterized by the deterioration of the macula, the central part of the retina responsible for sharp, detailed vision. This leads to a gradual and irreversible loss of central vision.[17]A defining feature in early stages of the disease is the presence of drusen, which are extracellular deposits that accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane.[8] The RPE is a critical layer of cells that supports the light-sensing photoreceptors of the retina.
As the disease progresses, these drusen may enlarge, become indistinct, and eventually resorb, leaving behind areas of retinal depigmentation.[8]In advanced stages of atrophic macular degeneration, there is a distinct atrophy of the RPE, leading to the death of photoreceptor cells.[20] This cellular dysfunction can be driven by various factors, including mitochondrial defects that contribute to degenerative retinal diseases. [31]Furthermore, studies indicate that altered gene expression in dry age-related macular degeneration, which encompasses atrophic forms, may suggest an early loss of choroidal endothelial cells, highlighting the involvement of surrounding ocular tissues in the disease process.[32]
Genetic Architecture and Susceptibility
Section titled “Genetic Architecture and Susceptibility”Genetic factors play a substantial role in the predisposition to atrophic macular degeneration, accounting for an estimated 50% of the disease’s heritability.[24] Numerous genetic loci and specific genes have been identified as contributors to increased risk. For instance, common variants in the ARMS2/HTRA1region are strongly associated with advanced age-related macular degeneration.[24] Other implicated regions include those near FRK/COL10A1 and VEGFA, where common genetic variants are linked to advanced forms of the disease , as well as specific variants within theTNXB-FKBPL-NOTCH4 region of chromosome 6p21.3. [6]These genetic findings highlight the complex molecular landscape underlying the disease, suggesting that multiple genes and their regulatory networks collectively influence an individual’s susceptibility and the rate of disease progression. Understanding these genetic predispositions is crucial for predicting risk and exploring targeted therapeutic strategies.
The Complement System and Inflammatory Response
Section titled “The Complement System and Inflammatory Response”One of the most significant biological pathways implicated in the pathogenesis of atrophic macular degeneration is the complement system, a crucial component of the innate immune response. Genetic studies have revealed an unanticipated and central role for this pathway in disease development.[24] Specifically, several genes encoding complement factors, including CFH (complement factor H), C2, CFB (complement factor B), C3 (complement component 3), and CFI (complement factor I), have been strongly associated with advanced forms of the condition. [24]
Polymorphisms, such as a variant in CFH, have been shown to significantly increase the risk of age-related macular degeneration.[17] Similarly, variations in the BF and C2genes are also linked to the disease.[33]The dysregulation of this pathway contributes to chronic inflammation and cellular damage within the macula, underscoring its pivotal role in the disease mechanism. This strong association has even spurred the development of clinical trials for drugs that modulate the complement pathway in patients with age-related macular degeneration.[24]
Metabolic and Extracellular Matrix Regulation
Section titled “Metabolic and Extracellular Matrix Regulation”Beyond inflammatory pathways, metabolic processes and factors affecting the extracellular matrix also play a critical role in the development and progression of atrophic macular degeneration. The high-density lipoprotein (HDL) pathway has been identified as an important contributor, with genetic variants in genes such asLIPC (hepatic lipase) and TIMP3(tissue inhibitor of metalloproteinases 3) influencing susceptibility to the disease.[24] These genes suggest a link between lipid metabolism and the accumulation of deposits in the retina.
TIMP3 is a key biomolecule known for its role in regulating extracellular matrix turnover, and its dysfunction can impact the structural integrity of Bruch’s membrane and the overall health of the RPE. [24] Additionally, the expression of growth factors like FGF5(fibroblast growth factor 5) has been observed in choroidal neovascular membranes associated with age-related macular degeneration.[31]While primarily associated with the neovascular (wet) form, the presence of such growth factors indicates a complex interplay of molecular signals that can contribute to advanced disease states, including those characterized by atrophy.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Immune and Inflammatory Response Dysregulation
Section titled “Immune and Inflammatory Response Dysregulation”The complement system plays a central and unanticipated role in the pathogenesis of atrophic macular degeneration, with genetic variants in complement pathway genes such asCFH, C2, CFB, C3, and CFIstrongly associated with the disease.[24] This complex cascade is a critical component of innate immunity, but its dysregulation can lead to chronic inflammation and cellular damage in the retina. Activation of the classical complement cascade, for instance, mediates central nervous system synapse elimination, and upregulation of complement component C1Q has been observed in the retina. [7]Furthermore, the molecular regulation of neuroinflammation, which is driven in part by complement pathway activity, is a key area of research for understanding disease progression and identifying new therapeutic targets.[34] Disrupting the complement cascade has been shown to delay retinal ganglion cell death in some contexts, highlighting its potential as a therapeutic intervention. [7]
Vascular and Extracellular Matrix Homeostasis
Section titled “Vascular and Extracellular Matrix Homeostasis”Atrophic macular degeneration involves significant alterations in vascular integrity and the extracellular matrix within the macula. Variants nearVEGFAare associated with advanced forms of the disease, reflecting the critical role of vascular endothelial growth factor signaling in retinal health and disease progression.[24] Similarly, PDGFB(Platelet-Derived Growth Factor B) has been identified through genome-wide pleiotropy studies to be associated with age-related macular degeneration, further implicating growth factor signaling in vascular maintenance.[32]Dysregulation of these pathways contributes to an early loss of choroidal endothelial cells, which is a hallmark of dry age-related macular degeneration.[35] Moreover, genes like FRK/COL10A1 and TIMP3 (Tissue Inhibitor of Metalloproteinases 3), which are involved in extracellular matrix remodeling, have variants associated with advanced AMD, emphasizing the importance of a balanced tissue environment. [24] The expression of FGF5(Fibroblast Growth Factor 5) is also noted in choroidal neovascular membranes, suggesting its involvement in abnormal vascular proliferation, which can complicate late-stage disease.[36]
Metabolic and Cellular Bioenergetics
Section titled “Metabolic and Cellular Bioenergetics”Metabolic dysfunction, particularly in energy metabolism and lipid homeostasis, is a significant contributor to atrophic macular degeneration. Genetic variants inLIPC, a gene involved in the high-density lipoprotein (HDL) pathway, are associated with AMD, indicating that altered lipid processing and transport play a role in disease susceptibility.[24] Mitochondria, the cellular powerhouses, are central to this metabolic dysregulation, with mitochondrial defects driving various degenerative retinal diseases by impairing energy production and increasing oxidative stress. [37] Key enzymes in the visual cycle, such as RDH5 (Retinol Dehydrogenase 5), which is expressed in the retinal pigment epithelium (RPE), are crucial for proper photoreceptor function; mutations in this gene are linked to conditions like cone dystrophy and night blindness, underscoring the importance of retinal energy and retinoid metabolism. [14] Another example includes SLC6A20, a proline transporter, whose variants have been associated with metabolites, suggesting broader metabolic impacts. [14]
Retinal Cell Signaling and Gene Regulation
Section titled “Retinal Cell Signaling and Gene Regulation”Complex signaling cascades and intricate gene regulatory mechanisms govern retinal cell survival and function, and their disruption contributes to atrophic macular degeneration. The ion channelTRPM1is expressed in retinal depolarizing bipolar cells and is a key component of the metabotropic glutamate receptor 6 signaling pathway, an essential vision-related pathway where interference can lead to blindness.[23] TRPM1 also regulates intracellular Ca2+ levels, and disturbed expression can lead to a drop in calcium concentrations, affecting cellular signaling. [23] The expression of TRPM1 and RLBP1 (Retinaldehyde Binding Protein 1), another gene associated with AMD, is proposed to be controlled by the microphthalmia-associated transcription factor, highlighting the hierarchical regulation of genes critical for retinal health. [23] Post-translational regulatory mechanisms, such as those involving microRNAs, also play a role; for example, downregulation of miR-145-5p has been shown to elevate retinal ganglion cell survival by targeting FGF5, offering a potential therapeutic avenue through gene regulation. [38] Additionally, genes like SKIV2L and MYRIP have been identified as protective factors for AMD. [10] MYRIP is known to enable the recruitment of myosin VIIa (MYO7A) to retinal melanosomes via RAB27A in retinal pigment epithelial cells, linking gene products to critical cellular processes such as melanosome transport and maintenance. [10] These examples illustrate the complex interplay of gene regulation, protein modification, and cellular signaling networks that are dysregulated in AMD, often through pleiotropic mechanisms where single genetic variants can influence multiple ocular diseases. [31]
Clinical Relevance
Section titled “Clinical Relevance”Diagnosis, Classification, and Prognosis
Section titled “Diagnosis, Classification, and Prognosis”Atrophic macular degeneration, particularly its advanced form known as geographic atrophy (GA), is a leading cause of irreversible vision loss in older adults. Comprehensive diagnostic evaluation utilizes multimodal imaging techniques, including optical coherence tomography (OCT), which provides detailed insights into retinal and choroidal thickness and structural integrity. These imaging modalities are fundamental for accurately diagnosing the disease, assessing its severity, and monitoring structural changes over time.[13]Standardized classification systems, such as the Three Continent Consortium (3CC) Severity Scale or the AREDS-9 step classification, are vital for consistent staging of early age-related macular degeneration (AMD) based on drusen characteristics and pigmentary abnormalities, which helps standardize clinical assessment and research efforts.[39]
The clinical course of atrophic macular degeneration is often slowly progressive, making prognostic indicators crucial for patient management. The presence of large drusen (exceeding 125 µm in diameter), especially those with indistinct borders or reticular patterns, extending over significant macular areas, strongly predicts an increased risk of progression to late, vision-impairing forms of the disease.[8]Furthermore, genetic studies, employing methods like robust Cox proportional hazards models, have identified specific genetic variants that influence disease susceptibility and progression, offering additional tools for prognostic assessment and predicting future visual outcomes.[20]
Risk Stratification and Personalized Approaches
Section titled “Risk Stratification and Personalized Approaches”Identifying individuals at elevated risk for developing or progressing to atrophic macular degeneration is a cornerstone of preventative and personalized medicine. Risk assessment integrates known clinical factors, extensively documented in large-scale studies such as the Age-Related Eye Disease Study (AREDS), with insights derived from genome-wide association studies (GWAS).[40] GWAS have pinpointed numerous genetic loci associated with both early and advanced stages of AMD, enhancing the understanding of its complex etiology and revealing distinct genetic differences between atrophic and neovascular subtypes. [8] This wealth of genetic information allows for a more refined risk prediction model that goes beyond traditional demographic and clinical markers.
The amalgamation of genetic and clinical risk factors facilitates the implementation of personalized medicine, enabling clinicians to develop tailored prevention strategies and monitoring schedules for high-risk individuals. [20]For example, a patient’s specific genetic profile could dictate the frequency of ophthalmic examinations or guide recommendations for lifestyle modifications aimed at delaying disease onset or slowing progression. This sophisticated risk stratification allows for a more targeted allocation of healthcare resources and customized patient education, fostering proactive and individualized care plans for atrophic macular degeneration.
Systemic Health and Comorbidities
Section titled “Systemic Health and Comorbidities”Atrophic macular degeneration is increasingly recognized not only as an ocular disease but also as a condition intertwined with broader systemic health. Research has demonstrated significant associations between AMD and various systemic comorbidities, including hypertension, ischemic heart disease, cardiac dysrhythmias, cerebrovascular diseases, chronic respiratory conditions, and hyperlipidemia.[22] These systemic links highlight the necessity of a holistic patient evaluation, as the management of these co-existing conditions may influence overall patient health and potentially affect the trajectory or systemic impact of AMD.
Furthermore, atrophic macular degeneration has been identified as an independent clinical risk factor for adverse outcomes from systemic infections, such as an increased risk of severe complications, including respiratory failure and mortality, in patients with COVID-19.[32] This suggests shared biological pathways or general physiological vulnerabilities that predispose individuals with AMD to more severe systemic health challenges. Genetic studies support this concept of pleiotropy, with examples such as the PDGFBgene being associated with both AMD and outcomes of COVID-19 infection, illustrating the intricate connections between ocular pathology and systemic health at a molecular level.[32]Therefore, clinicians should consider these wide-ranging systemic implications when providing care for patients with atrophic macular degeneration.
Frequently Asked Questions About Atrophic Macular Degeneration
Section titled “Frequently Asked Questions About Atrophic Macular Degeneration”These questions address the most important and specific aspects of atrophic macular degeneration based on current genetic research.
1. My parent lost central vision, will I definitely too?
Section titled “1. My parent lost central vision, will I definitely too?”While genetic predisposition plays a substantial role, contributing to an estimated 50% of the disease’s heritability, it’s not a definite guarantee. You might inherit some risk factors, but other genetic and environmental factors also influence whether you develop atrophic macular degeneration. Regular eye exams are important for monitoring your eye health.
2. Can I prevent this vision loss even with my family history?
Section titled “2. Can I prevent this vision loss even with my family history?”While you can’t change your genes, lifestyle factors can play a role alongside your genetic predisposition. Research indicates that things like smoking history and other environmental exposures interact with your genetics. Focusing on a healthy lifestyle can potentially help manage your risk, though it won’t entirely eliminate a strong genetic tendency.
3. Is getting a genetic eye test worth it for my future vision?
Section titled “3. Is getting a genetic eye test worth it for my future vision?”Genetic testing can be useful, as genetic factors contribute significantly to this condition. Predictive models incorporating your genetic profile, along with demographic data and environmental exposures, can help forecast your risk of progressing to advanced forms like geographic atrophy. This information can guide early monitoring and personalized risk assessment.
4. Does my ethnicity change my personal risk for this eye problem?
Section titled “4. Does my ethnicity change my personal risk for this eye problem?”Yes, your ethnic background can influence your risk. Much of the research has focused on people of European ancestry, and findings may not fully apply to other groups. For example, some Asian populations exhibit distinct clinical presentations of age-related macular degeneration and potentially different underlying genetic characteristics.
5. Why do some people get this central vision loss and others avoid it?
Section titled “5. Why do some people get this central vision loss and others avoid it?”It’s a complex interplay of genetic and environmental factors. About 50% of the risk is due to genetics, with specific genes related to your immune system’s complement pathway (like CFH or C3) and lipid metabolism (like LIPC or TIMP3) playing key roles. However, lifestyle choices and other environmental exposures also significantly contribute to who develops the condition and who doesn’t.
6. Can eating well or exercising prevent my eye disease if it’s genetic?
Section titled “6. Can eating well or exercising prevent my eye disease if it’s genetic?”While specific diets or exercises aren’t detailed for prevention, the interaction between your genes and environmental factors is important. A healthy lifestyle, including managing factors like smoking and general well-being, is generally beneficial. While your genetics set a baseline risk, positive lifestyle choices can help manage your overall health, potentially influencing disease progression.
7. If I have early signs, can a test predict how fast my vision will worsen?
Section titled “7. If I have early signs, can a test predict how fast my vision will worsen?”Yes, genetic factors can be integrated into predictive models. These models combine genetic information with demographic data, environmental exposures, and characteristics of your macula observed during eye exams. They can accurately forecast the progression from early and intermediate forms of macular degeneration to advanced geographic atrophy, helping anticipate future vision changes.
8. My sibling has good vision, but I have early signs. Why us?
Section titled “8. My sibling has good vision, but I have early signs. Why us?”Even within families, genetic inheritance can vary, and environmental factors differ. While about half the risk comes from shared genetics, you might have inherited different combinations of risk-factor genes than your sibling, such as variations in ARMS2/HTRA1or complement pathway genes. Additionally, individual environmental exposures and lifestyle choices also play a significant role.
9. Is it possible for doctors to predict who gets this severe eye condition?
Section titled “9. Is it possible for doctors to predict who gets this severe eye condition?”Yes, doctors can use predictive models that combine several pieces of information to estimate your risk. These models consider your genetic makeup, personal demographics, environmental factors like smoking history, and characteristics of your macula observed during eye exams. This helps identify individuals at higher risk of developing geographic atrophy.
10. Why aren’t all genetic risks for this eye problem known yet?
Section titled “10. Why aren’t all genetic risks for this eye problem known yet?”Current genetic studies, especially genome-wide association studies, have limitations in fully capturing all genetic risk factors. They might not cover low-frequency coding variants that can have significant functional impacts. Also, most research has predominantly focused on populations of European ancestry, meaning unique genetic patterns in other ethnic groups are still being uncovered.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Sobrin, L., et al. “Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.”Ophthalmology, vol. 119, 2012, pp. 1827–1835.
[2] Cheng, C.Y., et al. “New loci and coding variants confer risk for age-related macular degeneration in East Chinese.”Nature Communications, vol. 6, 2015, p. 7413.
[3] Yan, Q., et al. “Genome-Wide Analysis of Disease Progression in Age-related Macular Degeneration.”Hum Mol Genet, vol. 27, no. 4, 2018, pp. 748-57.
[4] Osterman, M.D., et al. “Genomewide Association Study of Retinal Traits in the Amish Reveals Loci Influencing Drusen Development and Link to Age-Related Macular Degeneration.”Invest Ophthalmol Vis Sci, vol. 63, 2022, pp. 23.
[5] Haines JL, Hauser MA, Schmidt S, et al. “Complement factor H variant increases the risk of age-related macular degeneration.”Science, vol. 308, 2005, pp. 419–21.
[6] Cipriani V, et al. “Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.”Hum Mol Genet, vol. 21, no. 15, 2012, pp. 3528-40.
[7] Scheetz TE. “A genome-wide association study for primary open angle glaucoma and macular degeneration reveals novel Loci.”PLoS One, vol. 8, no. 3, 2013, pp. e58657.
[8] Holliday EG, et al. “Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.”PLoS One, vol. 8, no. 1, 2013, pp. e53830.
[9] Naj AC, et al. “Genetic factors in nonsmokers with age-related macular degeneration revealed through genome-wide gene-environment interaction analysis.”Ann Hum Genet, vol. 77, no. 3, 2013, pp. 185-94.
[10] Kopplin LJ, et al. “Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration.”Genes Immun, vol. 11, no. 7, 2010, pp. 599-604.
[11] Bird, A.C., Bressler, N.M., Bressler, S.B., Chisholm, I.H., Coscas, G., Davis, M.D., de Jong, P.T., Klaver, C.C.W., Klein, B.E.K., Klein, R., et al. “An international classification and grading system for age-related maculopathy and age-related macular degeneration.”Survey of Ophthalmology, vol. 39, 1995, pp. 367–374.
[12] Winkler TW, et al. “Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease.”BMC Med Genomics, vol. 13, no. 1, 2020, pp. 119.
[13] Garrity, S.T., et al. “Multimodal imaging of Nonneovascular age-related macular degeneration.”Invest Ophthalmol Vis Sci, vol. 59, 2018, pp. AMD48–64.
[14] Gao, X. R. et al. “Genome-wide association analyses identify 139 loci associated with macular thickness in the UK Biobank cohort.” Hum Mol Genet, vol. 28, no. 7, 2019, pp. 1162–1172.
[15] Marmor, D.J., et al. “Simulating vision with and without macular disease.”Arch Ophthalmol, vol. 128, 2010, pp. 117–25.
[16] Wood, A., Binns, A., Margrain, T., Drexler, W., Povaˇzay, B., Esmaeelpour, M., Sheen, N. “Retinal and choroidal thickness in early age-related macular degeneration.”American Journal of Ophthalmology, vol. 152, 2011, pp. 1030–1038.
[17] Klein, R., et al. “Harmonizing the classification of age-related macular degeneration in the three-continent AMD consortium.”Ophthalmic Epidemiol, vol. 21, 2014, pp. 14–23.
[18] Swaroop, A., et al. “Unravelling a late-onset multifactorial disease: From genetic susceptibility to disease mechanisms for age-related macular degeneration.”Hum Mol Genet, vol. 18, no. R2, 2009, pp. R118-24.
[19] Hammond, C.J., et al. “Genetic influence on early age-related maculopathy: a twin study.” Ophthalmology, vol. 109, 2002, pp. 730–6.
[20] Chen, W. et al. “Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.”Proc Natl Acad Sci U S A, 2010.
[21] Fritsche, L.G., et al. “Seven new loci associated with age-related macular degeneration.”Nat Genet, vol. 45, no. 4, 2013, pp. 433-39.
[22] Shih, C.H., et al. “Genome-wide association study and identification of systemic comorbidities in development of age-related macular degeneration in a hospital-based cohort of Han Chinese.”Front Genet, vol. 14, 2023, p. 1113063.
[23] Persad, P.J., et al. “Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1.”Invest Ophthalmol Vis Sci, vol. 58, no. 9, 2017, pp. 3672-84.
[24] Yu, Y. et al. “Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.”Hum Mol Genet, 2011.
[25] Chakravarthy, U., et al. “Clinical risk factors for age-related macular degeneration: A systematic review.”Ophthalmology, vol. 117, 2010, pp. 1045-1050.e5.
[26] Cho, B.J., et al. “Prevalence and risk factors of age-related macular degeneration in Korea: The Korea national health and nutrition examination survey 2010-2011.”Invest. Ophthalmol. Vis. Sci., vol. 55, no. 2, 2014, pp. 744-51.
[27] Baird, P.N., et al. “Gene-environment interaction in progression of AMD: the CFH gene, smoking and exposure to chronic infection.”Hum Mol Genet, vol. 17, 2008, pp. 1299–305.
[28] Ayala-Haedo, J.A., et al. “Analysis of single nucleotide polymorphisms in the NOS2A gene and interaction with smoking in age-related macular degeneration.”Ann Hum Genet, vol. 74, 2010, pp. 195–201.
[29] Jager, R.D., et al. “Age-related macular degeneration.”N. Engl. J. Med., vol. 358, 2008, pp. 2606-17.
[30] Cherepanoff, S., et al. “Bruch’s membrane and choroidal macrophages in early and advanced age-related macular degeneration.”Br. J. Ophthalmol., vol. 94, 2010, pp. 917-20.
[31] Xue, Z. et al. “Genome-wide association meta-analysis of 88,250 individuals highlights pleiotropic mechanisms of five ocular diseases in UK Biobank.” EBioMedicine, 2022.
[32] Chung, J. et al. “Genome-Wide Pleiotropy Study Identifies Association of PDGFBwith Age-Related Macular Degeneration and COVID-19 Infection Outcomes.”J Clin Med, 2023.
[33] Gold, B. et al. “Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.”Nat Genet, 2006.
[34] Tezel, G. “Molecular regulation of neuroinflammation in glaucoma: Current knowledge and the ongoing search for new treatment tar-gets.” Prog Retin Eye Res, vol. 87, 2022, 100998.
[35] Whitmore, S. S. et al. “Altered gene expression in dry age-related macular degeneration suggests early loss of choroidal endothelial cells.”Mol. Vis., vol. 19, 2013, pp. 2274–2297.
[36] Kitaoka, T. et al. “Expression of FGF5 in choroidal neovascular membranes asso-ciated with ARMD.” Curr Eye Res, vol. 16, no. 4, 1997, pp. 396–399.
[37] Ferrington, D. A. et al. “Mitochondrial defects drive degenerative retinal diseases.” Trends Mol Med, vol. 26, no. 1, 2020, pp. 105–118.
[38] Zhang, J. et al. “Downregulation of miR-145-5p elevates retinal ganglion cell survival to delay diabetic retinopathy prog-ress by targeting FGF5.”Biosci Biotechnol Biochem, vol. 83, no. 9, 2019, pp. 1655–1662.
[39] Winkler, TW., et al. “Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease.”BMC Med Genomics, vol. 12, 2019, p. 146.
[40] AREDS Research Group. “Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: age-related eye disease study report number 3.”Ophthalmology, vol. 107, 2000, pp. 2224–32.