Genetics of Age-Related Macular Degeneration

Updated: Apr 08, 2015
  • Author: Lucia Sobrin, MD, MPH; Chief Editor: Karl S Roth, MD  more...
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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. [1] The risk of developing the disease is three-fold higher in people who have a family member with AMD than in those without a first-degree relative with AMD. [2]

Since 2005, 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. [3, 4, 5, 6, 7]

Several other genetic loci in the alternative complement cascade have also been consistently shown to affect AMD risk. These include other variants in CFH, [8] as well as other genes: factor B (BF)/complement component 2 (C2), [8, 9] complement component 3 (C3), [10, 11] and complement factor I (CFI). [12, 13, 14, 15]

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. [16, 17, 18] 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. [19]

Most recently, hepatic lipase C (LIPC) and tissue inhibitor of metalloproteinase 3 (TIMP3) were reported to be associated with AMD in large genome-wide association studies. [20, 21] LIPC, a novel AMD gene, is involved in high-density lipoprotein cholesterol (HDL) metabolism, [20, 22] and TIMP3 is implicated in a Mendelian, early-onset form of macular degeneration known as Sorsby's fundus dystrophy. [23]

The relationship among environmental risk factors, these genetic variants, and AMD has also been explored. In one study, the susceptibility to advanced AMD associated with CFH Y402H was modified by body mass index (BMI), and both BMI and smoking increased the risk of advanced AMD within the same genotype. [24] However, statistical interactions between smoking and either the CFH Y402H or HTRA1/ARMS2 genotypes have not been observed. [24, 25]


Clinical Implications

Even prior to the identification of the genetic associations described above, the inflammatory cascade had already been thought of as an important component in the pathophysiology of AMD, [26, 27, 28] and a study showed that a marker of systemic inflammation, C-reactive protein, was related to AMD. [29]

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. [30] 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.

Following on these complement-related genetic discoveries, various complement-modulating agents are currently in clinical trials for the treatment of AMD. [31]

  • C3 inhibitor intravitreal compstatin/POT-4: phase 1 clinical trials in the treatment of wet AMD have been completed, and trials in dry AMD are being planned;

  • Anti-C5 antibody eculizumab: systemic administration is being investigated for geographic atrophy in an ongoing phase 2 clinical trial;

  • C5 inhibitor ARC1905: intravitreal administration is being examined for the treatment of both dry and wet AMD in phase 1 clinical trials;

  • Antibody against complement factor D: intravitreal administration has completed phase 1 clinical trials for geographic atrophy.

Other complement-modulating agents in preclinical development include an antibody against BF, recombinant CFH, and a soluble form of complement receptor 1.

As more is learned about the role of the other genes associated with AMD, additional therapeutic avenues may be open. In particular, it appears that several HDL-related loci in addition to LIPC are likely to be associated with AMD. [20, 21] Dissection of the mechanisms through which HDL mediates AMD risk may illuminate additional treatment strategies.

Currently, the primary treatment for wet AMD is intravitreal injection with VEGF inhibitors. Currently, ranibizumab (Lucentis) has FDA approval, whereas bevacizumab (Avastin) is used on an off-label basis. [32]

The FDA issued a safety alert regarding repackaged intravitreal injections of bevacizumab (Avastin), an anti-VEGF antibody. Serious eye infections caused by Streptococcus endophthalmitis have been reported in 12 patients who received the injections. The infections were the result of 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. [33]

Strategies to prevent the conversion from dry AMD to wet AMD include high-dose consumption of vitamins and minerals and a healthy diet and lifestyle, which promote vascular health. [34]


Genetic Testing

The genetic variants discovered to date 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. [35] However, there is no consensus yet on how genetic testing should be integrated into clinical practice.

Further validation of genetic testing for predicting AMD development and progression will occur as additional genetic risk variants are discovered. Eventually, 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. [36]