March 2016




Retina consultation corner

On the AMD plate

by Maxine Lipner EyeWorld Senior Contributing Writer


I think its exciting and provocative, but I think that we have a lot of work to do before we head into clinical trials. But it makes biologic sense, and I think the hypothesis is intriguing. Amy Millen, PhD


Those who are deficient in vitamin D may be more prone to develop AMD.

Source: National Eye Institute

Eyeing vitamin D levels in connection with disease development

There appears to be many ways that adequate nutrition can support eye health. Having sufficient vitamin D status may be one of them, according to Amy Millen, PhD, associate professor, Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, N.Y. In a study published in the October 2015 issue of JAMA Ophthalmology, investigators found that women who were deficient in vitamin D might be more vulnerable to age-related macular degeneration (AMD). In particular, those without adequate vitamin D who also carried a high-risk genotype for complement factor H had a 6.7 greater risk of developing the disease, Dr. Millen reported.

This was something that Dr. Millens group had previously considered. Our research group had done 2 previous papers in this area, Dr. Millen said. In this earlier work looking at peoples vitamin D levels in conjunction with their AMD status, the group found a protective association, she noted. However, a limitation to the existing work is their cross-sectional design, investigating associations between vitamin D status and AMD at only 1 point in time. The impetus for this initial work came from mounting evidence suggesting that inflammation is involved in developing macular degeneration and that vitamin D has anti-inflammatory properties, Dr. Millen explained. We know vitamin D to be related to bone health and involved in the uptake of calcium and calcium homeostasis, she said, adding that evidence has been building that vitamin D plays other roles in the body.

Intrigued by vitamin D

Part of what has spurred interest is the fact that vitamin D receptors have been found in other areas besides the bones, kidneys, and intestines, Dr. Millen explained. People question why the vitamin D receptor is found in other parts of the body, she said. Also, there has been research showing that vitamin D has anti-inflammatory effects and is involved in angiogenesis. In addition to new blood vessel formation in cancer cases, such neovascularization plays a role in advanced macular degeneration. As part of the recent study, investigators analyzed data on approximately 1,700 women ages 54 to 74 who took part in the Carotenoids in Age-Related Eye Disease Study (CAREDS); CAREDS is ancillary to the larger Womens Health Initiative (WHI) investigation. [The women] came in for a study visit and we took eye photos. We also assayed stored blood drawn 6 years prior to CAREDS at a previous WHI study visit for 25-hydroxyvitamin D, Dr. Millen said. This is a biomarker for vitamin D status, and it reflects D thats coming from sunlight and from foods and supplements. In the study, investigators defined deficient levels of vitamin D as those less than 30 nanomoles per liter. This is the level that the Institute of Medicine defines as being deficient with respect to bone health, Dr. Millen explained, adding that investigators went with this because they didnt have any criteria as to what would be considered deficient for macular degeneration. One group not included here was women over age 75. Thats because no protective level of blood serum levels of vitamin D was seen in this older age group, Dr. Millen explained. We think they may have had competing risks and died from other diseases or were diagnosed with a chronic disease and changed their behavior, which made it look as if their vitamin D levels were higher than they had been during the majority of their life, she said. For these reasons we didnt look at the older women.

At increased risk

In those under age 74, investigators found increased risk for AMD in women who were deficient in vitamin D. What we saw is women tended to not have increased odds of AMD until their 25-hydroxyvitamin D levels were deficient, then their odds of getting AMD increased, Dr. Millen said. Vitamin D levels of less than 30 nanomoles per liter did not seem to be good for bones or for eyes.

In addition, investigators took it a step further to see if the association between vitamin D and AMD varied depending on an individuals genetic risk for AMD. Dr. Millen and co-authors examined the vitamin D and AMD association in women with differing levels of genetic risk defined by the Y402H variant of the gene complement factor H. In women who had low D and 2 alleles for the high-risk gene variant, there was about a 6-fold increased chance of AMD compared to women who had adequate vitamin D levels and no high risk alleles for complement factor H, Dr. Millen said. Scientists hypothesize that the body mounts a localized immune response to drusen. If the participant is not sufficient in D, it might impede the bodys ability to dampen that immune response in the eye, Dr. Millen said. A localized inflammatory response to drusen is not healthy for the eye. We speculate that maintaining a healthy vitamin D status may help individuals with AMD control that immune response that (otherwise) could lead to further damage. The take-home message here is for those who have low vitamin D status: A deficient vitamin D status could be related to increased odds of developing AMD, Dr. Millen reported, adding that for those who are already genetically at high risk, this association may be even stronger. This is just another bit of evidence suggesting that nutrition is important to eye health, she said. But its hard in an observational study to tease out or control for the many lifestyle factors that are also related to vitamin D levelsso someone with high D status probably has a healthy diet and is physically active. Investigators here tried to adjust for this, but Dr. Millen acknowledged that there is always some residual confounding or imperfect adjustment that may exist.

Overall, Dr. Millen views the results here as important for the future. I think its exciting and provocative, but I think that we have a lot of work to do before we head into clinical trials, she said. But it makes biologic sense, and I think the hypothesis is intriguing. From a clinical perspective, she concluded that it seems as if low levels of vitamin D could be detrimental when it comes to AMD; however, above the deficient threshold, increasing these levels may not be beneficial.


1. Millen AE, et al. Association between vitamin D status and age-related macular degeneration by genetic risk. JAMA Ophthalmol. 2015;133(10):11719.

Editors note: Dr. Millen has no financial interests related to her comments.

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