Do Genes Alter Response to AREDS Supplements? New Study Fuels Debate; Routine Testing Still Premature

Do Genetic Factors Alter the Response to AREDS Supplements?

The impact of the AREDS nutritional supplements on the rate of progression to advanced AMD for patients within specific genotype groups has been the subject of debate. Studies evaluating whether the effects of AREDS treatments (zinc alone, antioxidants alone, or both combined) differ according to genotype have produced conflicting results. A new analysis from Tufts University continues the debate, but does not clarify this complex issue.

The new retrospective study (1) by Johanna Seddon and colleagues differs from previous studies in that the analytical method selected, survival analysis, evaluated individual eyes instead of the participant as the unit of analysis.

Among 4124 eyes (2317 participants with available genetic samples), 882 progressed to overall advanced disease (both neovascular and geo-graphic atrophy). The investigators assessed the effect of supplementation on AMD outcomes, and interaction effects between supplement treatment groups and two AMD-related genotypes: Complement factor H (CFH) Y402H, and age-related maculopathy susceptibility 2 (ARMS2) A69S. 

Looking at the genotyped cohort as a whole, the zinc alone treatment had a beneficial effect on progression to neovascular AMD (HR: 0.65, p = 0.004), as did the combined antioxidant and zinc treatment (HR: 0.71, p = 0.024). There was no significant effect on geographic atrophy. A protective effect of the antioxidant treatment for progression to overall advanced disease was also noted (HR: 0.79, p = 0.025).

Among those taking the combined zinc and antioxidants treatment, a lower risk of progression to overall advanced disease was seen in those with a non-risk genotype for CFH (TT) vs. placebo (HR: 0.55, p = 0.033), and progression to neovascular disease (HR: 0.34, p = 0.004). 

No significant treatment effect was apparent for those who were homozygous for the CFH risk allele (CC). 

A protective effect of the combined treatment on progression to advanced disease was also observed among high-risk ARMS2 (TT) carriers (HR: 0.52, p = 0.005), and for progression to neovascular AMD (HR: 0.38, p = 0.003).

Four genetic groups that combined the number of risk alleles for CFH Y402H and ARMS2 were also evaluated for interaction with AREDS supplements. Low risk was defined as having no risk alleles; high risk as having 1-2 risk alleles:

Only the low / high genetic risk group received a statistically significant benefit from the combined zinc and antioxidant treatment for progression to overall advanced AMD compared to the placebo (HR: 0.52, p = 0.039). Most of the benefit in the low / high group was derived from lowering the risk of progression to neovascular disease. 

The authors conclude that the effectiveness of antioxidant and zinc supplementation may differ by genotype. No harmful effects of combined supplementation were apparent in these analyses.

It seems fairly clear that genetic susceptibility can modify the risk of progressing to advanced AMD. However, it is still not clear whether an individual’s genotype can alter the effectiveness of zinc plus antioxidant treatment. In contrast to the findings of the present analysis, no significant interaction between supplement treatment and genetics was seen in an AREDS analysis by Chew, et al (2).

Genetic Testing in the Clinical Setting Premature
 
Do the findings by Seddon, et al. support the use of genetic information for patients at risk of AMD in the clinical setting? And should genetic information be used to guide the choice of supplemental therapy? Not according to the Academy of Ophthalmology Task Force on Genetic Testing, who currently advise against routine testing, and not in the view of a comprehensive new review of AMD genetics for the clinician (3). [To access full article: https://www.dovepress.com/genetics-and-age-related-macular-degeneration-a-practical-review-for-t-peer-reviewed-fulltext-article-OPTH].

The new review underscores the complex nature of AMD, which has both genetic and environmental risk factors that interact in unknown ways. AMD genetic complexities are discussed and current research findings are put into perspective. The authors conclude that the bulk of the available peer-reviewed evidence suggests that genetic testing is more useful as a research tool than for clinical management of patients.

The article emphasizes that a randomized clinical trial (AREDS) designed to answer a specific question offers a higher level of evidence than do retrospective analyses from the same trial that attempt to answer a separate question.

Additionally, genetic association studies can often be misleading. For example, there are many patients with risk variants at both loci (CFH or ARMS2) that do not develop AMD, just as there are many patients who carry no risk variants at either loci who do develop the disease. Thus analyzing risk variants at only two loci (CFH and ARMS2) yields limited information, when 52 gene variants within 34 loci have been associated with AMD.

References

1. Seddon JM, et al. Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. Br J Ophthalmol. Published online first July, 2016.
2. Chew EY, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmol 14:121:2173-80, 2014.
3. Schwartz SG, et al. Genetics and age-related macular degeneration: a practical review for the clinician. Clin Ophthalmol, 10:1229-35, July 2016.

References