AMD Genetic Testing & AREDS Supplements

AMD Genetic Testing and AREDS Supplementation: Are Zinc-Free or Other Customized Supplements Really Warranted?

Why do SBH Macular products contain 80 mg of zinc?
In AREDS2, comparing formulas modified with low dose zinc (25 mg) vs. the original zinc dose (80 mg) showed no statistical difference for risk of progression. However a trend favoring greater protection was observed for the higher dose of zinc. Thus the NEI continues to recommend the higher dose, and MacularProtect Complete reflects the official recommendations of the NEI.

Why doesn’t SBH offer a zinc-free AREDS formula?
Two published studies (Awh et al) (1,2) have looked at genotype and the response to AREDS supplements, and concluded that zinc treatment in patients with CFH risk genotypes is associated with increased risk of AMD progression. SBH reviewed these and other relevant studies, which were also independently assessed by Elizabeth Johnson, PhD of the Jean Mayer USDA Human Nutrition Research Center on Aging, and Professor, Friedman School of Nutrition and Science Policy at Tufts University.

After careful and independent review, SBH concludes that current data is insufficient to make personalized supplement recommendations based on individual genotype—a conclusion consistent with that of the American Academy of Ophthalmology Task Force on Genetic Testing (3).

Importantly, the results of the 2 studies reporting a detrimental effect of zinc in those with CFH risk genotypes are in direct conflict with the results of two other studies evaluating this topic:

• Klein et al (4) found that all CFH genotypes (both high and low risk) benefited from zinc and antioxidants with no harm seen in those with CFH risk alleles;
• Chew et al (5) found that AREDS supplements (zinc plus antioxidants) reduced the rate of disease progression in all genotype groups—i.e. having a different genetic background had no impact on their response to AREDS supplements. Having CFH and ARMS2 risk genotypes did not significantly alter the benefits of the zinc and antioxidant combination.

What are the limitations and concerns related to the 2nd Awh et al study?
Several approaches used in the most recent, 2014 Awh et al study raise concerns about the validity of the findings. Notable examples include:

• Lack of statistical power
  Overall, the lack of statistical power is the biggest concern. Combining CFH and ARMS2 alleles as done in the Awh et al paper, very likely makes this problem worse. if a given SNP is relatively frequent then groups carrying the SNP are large, but if this group is combined with another SNP of low frequency (as in the Awh paper) then the second SNP could limit the size of the groups compared.  (A SNP is a site in the genome where a single DNA nucleic acid base – C, G, T, or U – can differ from person to person).

• Built-in bias in choosing subgroups for comparison
  Awh et al did not independently establish risk groups, which reduces bias. Instead, the method used in choosing subgroups raises the issue of selection bias. The genetic subgroups were not pre-specified, and were chosen from 9 different genetic subgroups created based on CFH and ARMS2 genes. These 9 subgroups were then organized based on rates of progression to late AMD. Using this method of selecting risk groups can produce results generated by selection bias and not true associations.


• Omission of important statistical adjustments
  Statistical values (‘p’ values) of the Awh paper were not corrected for the multiple tests performed. This is important because significant findings may be lost when the necessary correction for multiple testing is applied. (To reduce the chances of obtaining false-positive results when certain statistical tests are performed on a single set of data, an adjustment to p values, called the Bonferroni correction, is applied).

What is the NEI saying about the controversy?
According to Emily Chew, MD, a principal investigator of the AREDS and AREDS2 studies, the major problem in the second Awh paper relates to how the genotypic subgroups were selected. Finding statistically significant differences is almost a certainty when there are multiple groups (hence multiple comparisons) and when subgroup selection is based on outcome, she and her co-authors wrote in a short report published online November, 2014 (6). 

In that publication, Chew et al explain that Awh’s 2nd study was based on a subset of AREDS participants with available genetic information.  However Chew et al. had access to the genetic information of an additional 526 participants referred to as the "residual cohort".  Chew  used the residual cohort to test the validity of Awh’s findings. If the results of the residual cohort analysis were found to be in the same direction (either beneficial or harmful), and generally of the same magnitude as those published by Awh et al, this would validate Awh and his colleague’s analysis.

Chew et al’s analysis did not validate Awh’s findings. Quite the contrary. For all four of Awh’s genotypic groups, the combination of antioxidants and zinc was found to be beneficial and the treatment of choice in the residual cohort. 

The Chew et al paper also likened Awh’s subgroup selection based on outcome (progression to late AMD) to an analogy of dividing the population into subgroups based on their astrological sign.  One can easily demonstrate “statistical significance” by selecting those with the most beneficial treatment effects and those with the least beneficial effects, then comparing the two groups without accounting for multiple testing or for the lack of a pre-specified comparison. 

Using Awh’s cohort of patients, those born under the sign of Aries or Cancer were “harmed” by treatment with zinc, while the residual cohort that was not subjected to selection bias prior to analyses in the Chew et al study (5), showed no harmful effect of zinc for these astrological signs.

Graph Courtesy of: Ophthalmology

Dr. Chew cautioned against using genetic testing to decide whether patients should use an AREDS formula with or without zinc based on a statistically flawed, non-replicated retrospective analysis of existing data. That would deprive patients of a therapy proven to have significant public health impact, she and her fellow authors concluded. 

The authors of an accompanying editorial (7) in the same publication echo Chew et al's conclusion, emphasizing that Awh et al defined their genotype subgroups in a post hoc and improper manner. 

Update: (October, 2017)
To help resolve this controversy, three teams of bio-statisticians from Duke, MD Anderson, and Memorial Sloan Kettering Cancer Center independently assessed whether available evidence supports genetic testing before offering zinc and antioxidant supplements for those with AMD. Each team, working independently, performed a separate, complementary analysis of data obtained from the two original study teams (Chew et al and Awh et al). All three statistical groups concluded that genotyping of CFH and ARMS2 to guide AREDS supplement choice for the prevention of AMD progression is unwarranted. Read more.

1. Awh CW et al. CFH and ARMS2 Genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmol Aug. 20, 2013 [Epub ahead of print].  
2. Awh CC et al. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the age-related eye disease study. Ophthalmol [Epub ahead of print] Sept, 2014. 
3. AAO Task Force on Genetic Testing. Recommendations for Genetic Testing of Inherited Eye Diseases: Report of the American Academy of Ophthalmology Task Force on Genetic Testing—2012. Ophthalmol 119:2408-2410, 2012.
4. Klein ML et al. CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmol 115:1019-1025, 2008.
5. Chew EY et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements. AREDS report number 38. Ophthalmol [Epub ahead of print] June, 2014. 
6. Chew EY et al. Report: Genetic Testing in Persons with Age-Related Macular Degeneration and the Use of the AREDS Supplements: To Test or Not to Test? JAMA Ophthalmol [Epub ahead of print] November, 2014. 
7. Wittes J and Musch DC. Editorial: Should We Test for Genotype in Deciding on Age-Related Eye Disease Study Supplementation? JAMA Ophthalmol [Epub ahead of print] November, 2014.