Looking Back — and Ahead

The dean of AMD risk prevention research reflects on 25 years of progress and adds a unique perspective on current thinking.

By Johanna M. Seddon, MD, SCM

After initiating nutritional epidemiologic studies of AMD and cataract in the mid 1980s, my colleagues and I reported in 1994 that oral lutein¹ and zeaxanthin and omega-3 long-chain polyunsaturated fatty acids² could possibly reduce the risk of progression of AMD. However, during those early years, my talks were often scheduled at lunchtime, when some of the crowd was hungrier for alternatives. Since then, we have seen tremendous progress, including replication of those early findings. In 2001, AREDS showed the benefit of a combination of high-dose antioxidant vitamins and zinc.³ Here is a review of the progress we have made.

CONSIDERING NUTRITION

Besides our early research on lutein, zeaxanthin and omega-3 fatty acids, we conducted a study of 853 subjects in 2001 and found that a higher intake of specific types of fat, as well as total fat, was associated with a greater risk for advanced AMD.⁴ The implicated compounds included vegetable, monounsaturated, polyunsaturated and transunsaturated fats as well as linoleic acid. Another finding in the study was that diets high in omega-3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid, an omega-6 fatty acid, was low. We also found that higher levels of physical activity reduced risk.

These results are notable and suggested that AMD shared risk factors with cardiovascular disease,⁵ which had also been positively related to the intake of specific fats, including transunsaturated fats.⁶ Long-chain omega-3 fatty acids, especially docosahexanoic acid (DHA), found primarily in fish, had also been associated with an inverse risk for cardiovascular disease in some studies.⁷ The results of our study suggested a similar trend for AMD, but mainly among subjects who consumed lower levels of linoleic acid.

THEORIES ON FISH OIL

The implicated fats are typically concentrated in unhealthy, highly processed foods that may negatively affect the blood vessels that supply the choroid or retina. These and other foods might also increase oxidative damage in the macula. An additional study we completed in 2003 reinforced our earlier findings. In a prospective cohort study of 261 subjects, we sought to establish preventive measures by evaluating dietary fat intake as it related to the progression of early or intermediate AMD to advanced AMD associated with visual loss. We found that higher total fat intake and specific types of fats increased the risk of progression to the advanced forms of the disease. Fish intake and nuts reduced risk.⁸ Omega-3 fatty acids are known to reduce inflammation and inflammatory cytokines in the blood and may also have anti-angiogenic properties.⁹

MODIFYING RISK FACTORS

Not long ago, age was the only known risk factor for AMD, but smoking is now known to be important.^10-12 Thanks to continuing research by our team and others, we also know that poor eating habits also play an important role. Recommendations for a healthy diet are now part of the management of patients with AMD. Whether to promote supplements studied in AREDS1 (vitamin C, 500 mg; vitamin E, 400 IU; beta-carotene, 15 mg; zinc, 80 mg; and cupric oxide [copper], 2mg) or those still being evaluated by AREDS2 (no beta-carotene, lower zinc, lutein, zeaxanthin and omega-3 fatty acids) can be debated. I recommend supplements and foods rich in vitamin E, vitamin C, maybe D, and omega-3 fatty acids, in addition to lutein and zeaxanthin. The ingredients in the foods and supplements are the key factors, not specific brand names. This is part of a larger preventive health lifestyle of selecting healthy foods, avoiding certain types of fats, weight control, exercise, not smoking, and controlling blood pressure and cholesterol levels.⁵

ROLE OF GENES

As we demonstrated in our U.S. Twin Study of AMD, genetic factors play a substantial role in the etiology of AMD and associated macular characteristics, explaining 46% to 71% of the variation in the overall severity of the disease.¹³ We, and other research teams, are making remarkable progress in the study of genetics and AMD. A genetic effect in AMD has been confirmed by studies showing associations between AMD and several genetic loci.^14-25 More recently, LIPC and other genes in the HDL pathway and also TIMP3 have been discovered to be associated with AMD.^26,27 Adjusting for demographic and environmental variables in a study of 820 subjects (545 with advanced AMD and 275 with no AMD), we also found that the novel locus in the hepatic lipase (LIPC) gene is associated with reduced risk of advanced AMD independent of other genes and other risk factors. Lutein was protective independent of the gene effects. We included dietary lutein in our models because high-density lipoprotein (HDL) is the major lipoprotein transporter of lutein and zeaxanthin in the body, and the T allele of the LIPC gene increases HDL.^26,29-31 Therefore, both genetic susceptibility and behavioral and lifestyle factors modify the risk of developing AMD.

We have developed statistical models to predict who will progress from the early and intermediate stages of AMD to the advanced forms of geographic atrophy and neovascular disease. Our models include these genetic factors along with demographic (age, sex, education), environmental (smoking, BMI, and antioxidant use) and macular characteristics.^32-33 These models could become part of personalized medicine in the future.

Hot off the press is our article showing that common variants near two genes are associated with AMD, namely FRK/COL10A1 and VEGFA.³⁴ These are exciting times. We hope to find mechanisms and additional genetic pathways associated with AMD — and new therapies that work in those pathways.

IN ANOTHER 25 YEARS?

Our journey down this path of discovery began over 25 years ago. One can only marvel at the progress that will be made on this subject by research teams around the world in another 25 years — and discussed not only at some lunchtime podium among a few people, but distributed widely through the ever-advancing electronic media.

KEY POINTS TO REMEMBER ► Oral lutein and zeaxanthin and omega-3 long-chain polyunsaturated fatty acids could possibly reduce the risk of progression of AMD.1,2,4 ► AMD and cardiovascular disease appear to share risk factors and have been associated with the intake of specific fats, including trans-unsaturated fats.5-7 ► Cigarette smoking, increasing age, poor eating habits, lack of physical activity, hypertension, obesity, and high cholesterol are all risk factors for AMD.5,10-12,31 ► Genetic factors play a substantial role in the etiology of AMD and associated macular characteristics.13 ► A genetic effect has been confirmed by studies showing associations between AMD and several genetic loci.14-28,34 ► Lutein, serum HDL, and the LIPC gene are independently associated with AMD. Smoking and BMI are also independently related to AMD, controlling for genetic factors. Therefore, both genetic susceptibility and behavioral and lifestyle factors modify risk of developing AMD.28,32 Nutritional factors can modify or change your genetic susceptibility. ► Statistical models have been developed to predict who will progress from the early and intermediate stages of AMD to the advanced forms of geographic atrophy and neovascular disease.33,34

REFERENCES

1. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994;272(18):1413-1420.
2. Seddon J, et al. Dietary fat intake and age-related macular degeneration [ARVO abstract]. Invest Ophthalmol Vis Sci. 1994;35: #2003.
3. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
4. Seddon JM, Rosner B, Sperduto RD, et al. Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol. 2001;119(8):1191-1199.
5. Snow KK, Seddon JM. Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol. 1999;6(2):125-143.
6. Hu FB, Stampfer MJ, Manson JE, et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997;337(21):1491-1499.
7. Albert CM, Hennekens CH, O'Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA. 1998;279(1):23-28.
8. Seddon JM, Cote J, Rosner B. Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch Ophthalmol. 2003;121(12):1728-1737.
9. Seddon JM, Gensler G, Klein ML, Milton RC. C-reactive protein and homocysteine are associated with dietary and behavioral risk factors for age-related macular degeneration. Nutrition. 2006;22(4):441-443.
10. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA. 1996;276(14):1141-1136.
11. Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L. Smoking and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liées à l'Age. Arch Ophthalmol. 1998;116(8):1031-1035.
12. Mitchell P, Wang JJ, Smith W, Leeder SR. Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol. 2002;120(10):1357-1363.
13. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol. 2005;123(3):321-327.
14. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389.
15. Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424.
16. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.
17. 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. Proc Natl Acad Sci. USA 2005;102:7227-7232.
18. Jakobsdottir J, Conley Y, Weeks DE, et al. Susceptiblity genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet. 2005;77:389-407.
19. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet. 2005;14:3227-3236.
20. Maller J, George S, Purcell S, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006;38:1055-1059.
21. Souied EH, Leveziel N, Richard F, et al. Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population. Mol Vis. 2005;11:1135-1140.
22. Maller JB, Fagerness JA, Reynolds RC, et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007;39:1200-1201.
23.Yates JR, Sepp T, Matharu BK, et al. Genetic Factors in AMD Study Group. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553-561.
24. Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992-993.
25. Fagerness JA, Maller JB, Neale BM, et al. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet. 2009;17:100-1004.
26. Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci. USA 2010;107:7395-7400.
27. Chen W, Stambolian D, Edwards AO, et al. Genetic variants near TIMP3 and high-density lipoprotein associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci. USA 2010; 107:7401-7406.
28. Seddon J, Reynolds R, Rosner B. Associations of smoking, body mass index, dietary lutein, and the LIPC genetic variant rs10468017 with advanced age-related macular degeneration. Mol Vis. 2010;16:2412-2424.
29. Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56-65.
30. Curcio CA, Johnson M, Huang JD, Rudolf M. Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins. Prog Retin Eye Res. 2009; 28:393-422.
31. Reynolds R, Rosner B, Seddon JM. Serum lipid biomarkers and hepatic lipase (LIPC) gene associations with age-related macular degeneration. Ophthalmology. 2010;117:1989-1995.
32. Seddon J, Reynolds R, Maller J, et al Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009;50(5):2044-53.
33. Seddon JM, Reynolds R, Yu Y, Daly MJ. Predicting risk of progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology. 2011, in press.
34. Yu Y, Bhangale TR, Fagerness J, et al Common Variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet. Epub ahead of print: July 12, 2011.

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Dr. Seddon is a macular degeneration specialist and Director, Ophthalmic Epidemiology and Genetics Service at the New England Eye Center at Tufts Medical Center and Professor of Ophthalmology at Tufts University School of Medicine, Boston.