## Genetic Risk Factors in AMD **Key Point:** The complement factor H (CFH) gene polymorphism, particularly the Y402H variant, is the single strongest genetic risk factor for AMD identified to date. This accounts for approximately 50% of the genetic risk in AMD. ### Major Genetic Associations in AMD | Gene | Protein Function | Risk Mechanism | Population Impact | |------|-----------------|-----------------|-------------------| | **CFH (Chromosome 1)** | Complement pathway regulation | Impaired complement control → chronic inflammation | ~50% of genetic risk | | **ARMS2/LOC387715** | Mitochondrial import | Oxidative stress susceptibility | ~20% of genetic risk | | **C3 gene** | Complement component | Excessive complement activation | Moderate risk | | **HTRA1** | Serine protease | Extracellular matrix degradation | Moderate risk | ### Complement Pathway Involvement ```mermaid flowchart TD A[CFH polymorphism Y402H]:::outcome --> B[Impaired complement regulation] B --> C[Uncontrolled complement activation] C --> D[Chronic inflammation in choroid] D --> E[Drusen formation]:::action E --> F[RPE dysfunction]:::action F --> G[AMD progression]:::urgent ``` **High-Yield:** The CFH Y402H variant increases AMD risk 2-3 fold in heterozygotes and 4-5 fold in homozygotes. This is the most replicated genetic finding across multiple populations. **Mnemonic:** **CHARMS** — Complement, Heredity, Age, Retinal pigment epithelium dysfunction, Mitochondrial oxidative stress, Smoking - These are the major pathogenic pathways in AMD **Clinical Pearl:** Genetic testing for CFH is not routinely recommended for individual patient management but is important for understanding disease pathogenesis and identifying high-risk populations for preventive interventions. [cite:Harrison 21e Ch 328] 
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.