Diet can decrease the genetic risk of developing AMD A new study finds that high dietary intake of nutrients with antioxidant properties reduces the risk of early AMD in those at high genetic risk. Therefore, clinicians should provide dietary advice to young susceptible individuals to postpone or prevent the vision-disabling consequences of AMD.

The etiology of AMD is complex with both genetic and environmental factors contributing to pathogenesis. Inflammation and oxidative stress are known to be fundamental pathways. Complement factor H (CFH) and LOC387715/HTRA1 have been identified as the most prominent susceptibility genes. Carriers of the risk alleles of these genes have a significantly higher risk of AMD: the CFH Y402H variant increases the risk of AMD up to 11 times and the LOC387715 A69S variant, up to 15 times. Together, these variants contribute to late AMD in more than 80% of cases. To reduce the burden of this disease, it is therefore essential to find means to counteract these major gene effects.

The only protective factors for AMD known to date are nutrients. However, studies investigating interaction between nutrients and genetic risk have been relatively small and their results, inconsistent. Thus, whether the protection offered by these nutrients is sufficient to counteract the genetic risk is unclear.

Methods & Results

For 2167 individuals (≥55 years) from the population-based Rotterdam Study at risk of AMD, dietary intake was assessed at baseline using a semiquantitative food frequency questionnaire and genetic variants were determined using TaqMan assay. Incident early AMD was determined on fundus photographs at 3 follow-up visits (median follow-up, 8.6 years). The synergy index was used to evaluate biological interaction between risk factors; hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake and genotypes.

Five hundred seventeen participants developed early AMD over the course of the study.

Significant synergy indices supported the possibility of biological interaction between nutrient intake and genotype (FIGURE)

Homozygotes of CFH Y402H

• Zinc: Individuals in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27
  
• β-carotene: risk reduction from 2.54 to 1.47
  
• Lutein/zeaxanthin: risk reduction from 2.63 to 1.72
  
• EPA/DHA: risk reduction from 1.97 to 1.30

Since the frequency of LOC387715 A69S was lower than that of CFH Y402H, the number of participants in each stratum was low; the researchers therefore grouped all carriers of this variant to increase power to detect significant interaction.

Carriers of LOC387715 A69S

• Zinc: risk reduction from 1.70 to 1.17
  
• EPA/DHA: risk reduction from 1.59 to 0.95

Discussion & Conclusions

Modifying environmental factors is currently the only approach to reduce the genetic risk of AMD. Our study showed that higher dietary intake of zinc, ω-3 fatty acids, β-carotene, and lutein/zeaxanthin can attenuate the incidence of early AMD in those carrying important genetic risk variants. To achieve this benefit, it does not appear necessary to consume excessive amounts of these nutrients; the recommended dietary allowance will suffice.

Two other studies have examined interaction between genetic risk variants and nutrients in the development of AMD.

• In the AREDS antioxidant supplementation trial, Klein et al calculated the risk of progression to late AMD for the CFH Y402H and LOC387715 A69S genotypes in the various treatment arms. A high zinc dosage was most protective against AMD in noncarriers of the risk variant of CFH but produced the greatest, albeit nonsignificant, risk reduction in those carrying the risk variant of LOC387715.
  
• In the Blue Mountains Eye Study, a high fish intake resulted in a higher risk reduction in homozygous carriers of CFH Y402H than in noncarriers. However, this was not apparent for early AMD.

It is now well established that complement activation and inflammation play an important role in the pathogenesis of AMD. CFH is a key regulator of complement by inhibiting the alternative pathway and amplification phase of the cascade. The risk allele Y402H appears to impair this regulatory function of CFH, leading to complement overactivation, thereby increasing the risk of AMD.

The reason diet has an antagonistic effect in CFH Y402H carriers can be explained by several biological mechanisms, such as:

• Oxidative damage can activate the complement cascade by oxidation of fatty acids in retinal cell membranes. Nutrients with antioxidant properties will counteract this process by reducing the production of reactive oxygen species in the outer retina.
  
• Even after activation of the complement cascade, zinc may reduce terminal cell lysis by prohibiting binding of C9 to C5-8 and by preventing the formation of the membrane-attack complex.
  
• ω-3 Fatty acids have been described to lower acute-phase proteins (including complement C4, IgM, haptoglobin, C-reactive protein [CRP], and fibrinogen) and to function as an anti-inflammatory agent in the retina.

With respect to the LOC387715 gene, its increased risk of AMD conferred by the A69S variant is evident. Nevertheless, the precise mechanism has not been elucidated. Research evidence suggests that the A69S variant may jeopardize mitochondrial function and consequently lead to the formation of reactive oxygen species, apoptosis, and AMD. Nutrients may neutralize these oxygen radicals and reduce these devastating effects. Since zinc and EPA/DHA have multiple biological functions besides antioxidant (ie, anti-inflammatory and antiatherogenic), it is also possible that the interaction acts via 1 or more of these other mechanisms.

In conclusion, this study shows that high dietary intake of antioxidants, zinc, and ω-3 fatty acids may reduce the risk of early AMD among those at high genetic risk.

What diet is recommended? Fortified cereals, meats, dairy products, nuts, and seeds are a good source of zinc; dark-green leafy vegetables such as spinach and kale and orange vegetables including carrots and pumpkin are rich in ß-carotene and lutein/zeaxanthin; and oily fish such as herring, salmon, sardines, trout, and tuna provide EPA/DHA. These nutrients are all recommended in the Food Guide Pyramid and should be part of a regular diet for older adults. Given that there are no other interventions that are readily available, or offer prevention at such low cost, our findings stress the importance of sufficient intake of these nutrients in young susceptible individuals to postpone or prevent the devastating effects of AMD.


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Arch Ophthalmol. 2011 Jun;129(6):758-66