Diet can decrease the genetic risk of developing AMD
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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.
Arch Ophthalmol. 2011 Jun;129(6):758-66
http://www.ncbi.nlm.nih.gov/pubmed/21670343
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