Genetics of Age-Related Macular Degeneration

Updated: Feb 03, 2022
  • Author: Lucia Sobrin, MD, MPH; Chief Editor: Karl S Roth, MD  more...
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Practice Essentials

Age-related macular degeneration (AMD) is a common polygenic disease in which multiple genetic variants, as well as environmental and lifestyle factors, contribute to disease risk, each adding a small to moderate amount of increased risk. The risk of developing the disease is at least three-fold higher in people who have a family member with AMD than in those without a first-degree relative with AMD. This risk is amplified when immediate family members have the disease, with one study estimating a 27.8 times increased risk with an affected parent and 12 times increased risk for those with an affected sibling. [1, 2, 3, 4, 5, 6, 7]

Several genetic variants have been consistently associated with AMD. The common coding variant Y402H in the complement factor H (CFH) gene was the first identified. The odds ratio associated with being homozygous for the risk variant for all categories of AMD is estimated to be between 2.45 and 3.33; the odds ratios are higher, between 3.5 and 7.4, for advanced dry and wet forms of AMD. [8, 9, 10] Several other genetic loci in the alternative complement cascade have also been consistently shown to affect AMD risk. These include other variants in CFH, [11] as well as other genes: factor B (BF)/complement component 2 (C2), [11, 12] complement component 3 (C3), [13, 14] and complement factor I (CFI). [15, 16, 17, 18]

Several genes not involved in the complement cascade have also been implicated. Variation in the HTRA1/ARMS2 locus on chromosome 10 has been convincingly associated with AMD, with an effect size similar to or greater than that seen with CFH. [19] The function of this gene is not completely understood, but there is evidence that it confers greater risk for wet AMD than for geographic atrophy. [20]

Rare genetic variants in the complement system have also been found to play an important role in AMD. [21] Such rare variants have been described in the complement factor H (CFH), complement factor I (CFI), complement factor 9 (C9), and complement factor 3 (C3) genes. [22]

Hepatic lipase C (LIPC) and tissue inhibitor of metalloproteinase 3 (TIMP3) have been reported to be associated with AMD in large genome-wide association studies. [23, 24] LIPC, a novel AMD gene, is involved in high-density lipoprotein cholesterol (HDL) metabolism, [23, 25] and TIMP3 is implicated in a mendelian, early-onset form of macular degeneration known as Sorsby's fundus dystrophy. [3]

The International AMD Genomics Consortium discovered a total of 52 genetic variants that are associated with AMD. These variants are located among 34 loci. A genetic variant near MMP9 specific to the neovascular form of AMD was also identified. [21]

Management of exudative AMD may include the following [26, 27, 39] :

  • Intravitreal injection with faricimab, ranibizumab, bevacizumab, aflibercept, brolucizumab, or pegaptanib sodium
  • Photodynamic therapy with verteporfin
  • Thermal laser photocoagulation surgery
  • Antioxidant vitamin and mineral supplements (vitamin A, vitamin E, zinc, and lutein)
  • Wraparound shades (eg, orange-tinted, blue blocker lenses): Effective solution for delayed dark adaptation and to protect eyes from direct sunlight
  • Avoidance/cessation of tobacco use
  • Frequent follow-up for risk assessment of conversion to exudative AMD

Clinical Implications

Even before the identification of the genetic associations described above, the inflammatory cascade had been thought to be an important component in the pathophysiology of AMD, [28]  and a study showed that a marker of systemic inflammation, C-reactive protein, was related to AMD. [3]  The existence of multiple, complement-related AMD risk alleles has lent further support to this theory and has shed light on the role of uncontrolled alternative complement pathway activation in this disease.

CFH inhibits the alternative complement pathway by blocking formation and accelerating the decay of alternative pathway C3 convertases; it also serves as a cofactor for the factor-1 mediated cleavage and inactivation of C3b. [29] The Y402H variant is within the CFH binding site for heparin and C-reactive protein. Binding to these sites increases the affinity of CFH for C3b, which, in turn, increases the ability of CFH to inhibit complement's effects.

On the basis of these complement-related genetic discoveries, various trials have been performed for complement-modulating agents, [30]  such as C3 inhibitor intravitreal compstatin/POT-4, anti-C5 antibody, C5 inhibitor ARC1905, antibody against complement factor D, antibody against BF, recombinant CFH, and a soluble form of complement receptor 1.

The FDA issued a safety alert regarding repackaged intravitreal injections of bevacizumab (Avastin), an anti-VEGF antibody. Infections resulted from contamination that occurred during the repackaging of bevacizumab from 100 mg/4 mL single-use, preservative-free vials into individual 1-mL syringes for off-label use to treat wet macular degeneration. [31]


Genetic Testing

The genetic variants explain about half of the classical sibling risk of AMD, and commercial genetic testing for some AMD risk variants is currently available. Knowledge of genetic variation at risk loci increases the ability to predict AMD progression above and beyond knowledge of demographics, ocular factors, smoking history, and BMI. [2, 4, 32]

Genotyping may become a useful tool for identifying individuals who are at higher risk for disease and thus may benefit from more intense monitoring and/or preventive treatment strategies. Results from several well-powered, ongoing pharmacogenetic studies should clarify whether genetic make-up influences response to treatment in AMD, as suggested by some studies. [33, 32]