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Antioxidants, Zinc & Omega-3s Reduce Genetic Risk of Early AMD

Introduction: Genes, Nutrients and AMD Risk

AMD is clearly a complex disease with multiple environmental and genetic risk factors. In terms of genetics, two of the more prominent AMD susceptibility genes identified to date are Complement Factor H (CFH) and LOC387715 / HTRA1.

There are several different forms (variants) of these genes that significantly raise the risk of AMD. Carrying the CFH Y402H variant increases risk of AMD up to 11 times. For carriers of the variant LOC387715 A69S, the risk is up to 15 times greater.

Together, these variants may contribute to late AMD in more than 80% of cases. Thus finding ways to counter these major gene effects is of public health importance.

The only protective factors for AMD known to date are nutrients. Zinc and antioxidants were shown in the AREDS trial to reduce the risk of progression from intermediate to advanced AMD. Population based studies have also found a reduction in AMD risk progression with higher intakes of lutein/zeaxanthin, or with higher intakes of the omega-3 fatty acids EPA and DHA.

Is the protection afforded by these nutrients sufficient to reduce AMD risk in carriers of well-known risk variants? To address this question, authors of The Rotterdam Study have explored the relationship between a healthy diet, genetic risk and early AMD in a nested, case-control study (1).

Study Design

Dietary intake was assessed at baseline using a food frequency questionnaire for 2167 participants (> 55 years) at risk of AMD from the population-based Rotterdam Study. Genetic variants were determined using TaqMan assay. Incident early AMD was determined by fundus photography at 3 follow-up visits.

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 (stratified by tertiles) and genotypes.

Results

During a median follow-up of 8.6 years, 517 participants developed early AMD. Significant synergy indices supported a biological interaction between:

• CFH Y402H and Zinc, beta carotene, lutein/zeaxanthin, and EPA/DHA (p < .05).
• LOC 387715 A695 and Zinc, and EPA/DHA (p < .05).

Homozygotes of CFH Y402H with Zinc intake in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of beta carotene, lutein / zeaxanthin, and EPA / DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. (See table).

Graphic courtesy of Archives of Ophthalmology

Carriers of LOC387715 A69S with the highest intake of Zinc and EPA / DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all p trends < .05).

Comments

These results suggest that higher dietary intake of Zinc, carotenoids and EPA/DHA can attenuate the incidence of early AMD in those carrying important genetic variants. The authors conclude that “clinicians should provide dietary advice to young, susceptible individuals to postpone or prevent the vision-disabling consequences of AMD”.

It’s well established that complement activation and inflammation play an important role in development of AMD. The CFH gene is a key regulator of complement, and the Y420H variant impairs its regulatory function. As for LOC387715, evidence suggests that the A69S variant may jeopardize mitochondrial function and lead to free radical formation and apoptosis.

There are plausible mechanisms that could explain the effect of these nutrients in carriers of both variants. For example, antioxidant nutrients can counter oxidative damage, an activator of the complement cascade, while omega-3s act as anti-inflammatory agents in the retina. Dysfunctional mitochondria may increase complement activation which, evidence suggests, Zinc may counter.

References

1. Ho L, et al. Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and ω-3 fatty acids. The Rotterdam Study. Arch Ophthalmol 129:758-66, 2011.