Genetic Testing in Age-Related Macular Degeneration and AREDS Supplement Use
Genetic investigations in age-related macular degeneration (AMD) have increased exponentially since the discovery of the association of complement factor H (CFH) and AMD in 2005.1-4 However, despite the discovery of many more associated genotypes,5,6 we do not understand the pathobiology of the genetic associations. Research evaluating the influence of genotype on the response to anti-vascular endothelial growth factor therapies in eyes with neovascular AMD produced mixed results.7-11 Genetic associations have not been demonstrated to add to the clinical features (including visual acuity at the time of initiation of treatment, lesion size, and the duration between onset of symptoms and therapy) with respect to factors that may be important in determining visual acuity results following therapy.
Genetic testing for AMD prior to supplementation with the Age-Related Eye Disease Study (AREDS) supplements was recommended by Awh et al, based upon a retrospective analysis of data from a subgroup of AREDS participants.12 In two separate reports,12,13 Awh and colleagues suggested that treatment with zinc could be harmful in patients with certain genotypes and may accelerate the development of late AMD. In the second report, Awh and colleagues reclassified the genetic groups and re-analyzed the same data from this subgroup of AREDS participants. They analyzed each component of the AREDS supplement (antioxidant vitamins, zinc, and the combination of the antioxidants and zinc). In this second report,13 they found not only zinc alone but the combination of zinc and antioxidant vitamins may be harmful in persons with certain CFH risk alleles.
The AREDS investigators found no significant influence of genotype on the response to AREDS supplements.14 In response to the second report by Awh et al, the AREDS investigators were able to assemble another group of AREDS participants who were not part of the cohort analyzed by Awh et al.15 Using the exact genetic groupings assessed by Awh et al, the results of the analyses conducted by the AREDS investigators’ analyses did not replicate the findings of Awh et al. The AREDS investigators found a beneficial effect to the AREDS supplement in all the genotype groups defined by Awh et al. The conflicting results of these reports by Awh et al and the AREDS investigators were carefully interpreted in an outstanding editorial by Wittes and Musch,16 who wrote: “The genetic subgroups in the report by Awh et al13 are both post hoc and improper. The approach that Awh et al13 used in defining their genotype subgroups is circular: after selecting post-randomization outcomes observed by Awh et al12 to define subgroups in the study by Awh et al,13 they then tested those subgroups with the very same data.” Wittes and Musch agree with the recommendation of the AREDS investigators that persons with intermediate AMD (bilateral large drusen) or late AMD in one eye should consider taking the AREDS supplement, regardless of genotype. No genetic testing should be conducted prior to initiating the AREDS supplement as such analyses were only reasonable for generating new hypotheses to be tested. Prospective evaluations of this research question are required before implementing genetic testing. The AREDS investigators still believe, however, that genetic testing is important in research and may help us understand the pathogenesis of AMD and eventually uncover pathways for targeted therapies for both prevention and treatment of AMD.
Financial Support: Supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health, Department of Health and Human Services, Bethesda Maryland (contract HHS-NOI-EY-0-2127) The sponsor and funding organization participated in the design and conduct of the study; data collection, management, analysis and interpretation; and the preparation, review and approval of the manuscript. Conflicts of Interest: Emily Chewhas no conflicts of interest. The AREDS Study was sponsored by the NIH. The NIH holds a royalty-bearing license issued to Bausch and Lomb for the Age-Related Eye Disease Study Supplement.
1. Klein RJ, Zeiss C, Chew EY, Tsai J-Y, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris Fl, Ott J, Barnstable C, Hoh J. Complement Factor H polymorphism in age-related macular degeneration. Science. 2005 Apr 15;308(5720):385-9. Epub 2005 Mar 10.
2. Edwards AO, Ritter R, 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424. Epub 2005 Mar 10.
3. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proceedings of the National Academy of Sciences of the UnitedStates of America. 2005;102:7227-7232.
4. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005 Apr 15;308(5720):419-21. Epub 2005 Mar 10.
5. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration. Nature Genetics. 2013;45:433-439e2.
6. Fritsche LG, Fariss RN, Stambolian D, Abecasis GR, Curcio CA, Swaroop A. Age-Related Macular Degeneration: Genetics and Biology Coming Together. Annual Review of Genomics and Human Genetics. 2014Apr 16. [Epub ahead of print]
7. Brantley MA Jr, Fang AM, King JM, et al. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology. 2007;114:2168-73.
8. Lee AY, Raya AK, Kymes SM, et al. Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol. 2009;93:610-3.
9. Francis PJ. The influence of genetics on response to treatment with ranibizumab (Lucentis) for age-related macular degeneration: the Lucentis Genotype Study (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2011;109:115-56.
10. Orlin A, Hadley D, Chang W, et al. Association between high risk disease loci and response to anti-vascular endothelial growth factor treatment for wet age-related macular degeneration. Retina. 2012;32:4-9.
11. Hagstrom SA, Ying GS, Pauer GJ, et al; Comparison of AMD Treatments Trials Research Group. Pharmacogenetics for genes associated with age-related macular degeneration in the comparison of AMD treatments. Ophthalmology. 2013;120:593-9.
12. Awh CC, Lane A-M, Hawken S, et al. CFH and ARMS2 genetic polymorphism predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120:2317-23.
13. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology. 2014 Sep 4. [Epub ahead of print].
14. Chew EY, Klein ML, Clemons TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS Report Number 38. Ophthalmology. 2014;121:2173-80.
15. Chew EY, Klein ML, Clemons TE. Genetic testing in persons with age-related macular degeneration and the use of AREDS supplements: to test or not to test? Ophthalmology. ( http://www.aaojournal.org/article/S0161-6420(14)01012-4/abstract)
16. Wittes J, Musch DC. Should we test for genotype in deciding on Age-Related Eye Disease Study Supplementation? Ophthalmology. 2015 Jan;122(1):3-5.
About our author(s):
Emily Y. Chew, MD
Clinical Trials Branch, Division of Epidemiology and Clinical Applications
National Eye Institute/National Institutes of Health