AS257 - Nutritional and Genetic Risk Factors for Age-related Macular Degeneration
[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]
Investigator Names and Contact Information
Julie Mares [jmarespe@wisc.edu]
Introduction/Intent
Aging of the retina of the eye promotes the development of macular degeneration (AMD), a common cause of visual loss and health care expenditures in older Americans, particularly older women. The totality of scientific evidence from animal studies, clinical trials and observational studies suggests that nutrition is one of the most promising means to prevent or slow AMD, aside from smoking cessation. We are currently funded to evaluate relationships of vitamin D status to AMD risk, relationships that have been previously studied in only one other sample in which they were associated with reduced risk. We are evaluating the degree to which overall aspects of healthy eating reduces risk.
Three papers that describe these findings have either accepted for publication (1) or have are in the process of review by coauthors and the WHI Publications and Presentation Committee prior to submission.(2, 3), completing the Aims of the current funding period. These analyses were being performed in a sample of women participating in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative (WHI). This sample of women (n=1,787) from WHI observational study cohorts in Portland, OR, Iowa City, IA and Madison, WI, ages 50-79 years, previously provided extensive nutritional, lifestyle and medical data since 1994-97 and additional data, including photography of the retina in 2001-2004.
Recent evidence has identified candidate genes which explain a large amount of variability in risk for AMD. Thus, including indicators of genetic susceptibility could explain extraneous variation in AMD risk, could remove confounding, and/or could modify relationships of nutrition status to AMD. Therefore, we plan to extract DNA from stored lymphocytes to analyze variants for three candidate genes which most explain risk for AMD in other samples. Women will be ranked for genetic susceptibility by the joint presence of variants which increase risk for AMD.
This rank will be used in risk factor models to more closely evaluate nutritional risk for AMD, considering possible enhanced power available after removing variation due to genetic susceptibility and controlling for potential confounding or effect modification of nutritional status to AMD conferred by variation in genetic susceptibility. These studies are expected to enhance our ability to develop practical public health recommendations that integrate the many aspects of diet which may slow the development of age-related macular degeneration. This evidence may also strengthen recommendations for modification of nutritional risk according to a person's genetic predisposition for developing AMD.
Specific Aims
A broad array of nutrition risk and protective factors are being studied in relation to prevalence of AMD as part of the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women's Health Initiative (WHI). AMD was previously determined from retinal photographs taken in 2001-04 in 1,787 women who participated previously in CAREDS.
Unique to this sample are the availability of estimates of vitamin D status, retinal carotenoids and overall diet patterns. This supplements estimates of levels of nutrients in blood samples, foods and supplements that were collected in 1994-97, as part of WHI baseline investigations and levels of nutrients in foods and supplements in 1986-1990 and 2001-2004 collected in CAREDS. Thus, the nutritional data available to examine relationships to AMD risk is broader and deeper than that which is available in any other epidemiological study of AMD.
The present investigation extends these studies to include an assessment of genetic risk for AMD that is obtained by identifying the presence of variants in candidate genes which have been demonstrated to explain a large amount of AMD risk in other samples. Women will be ranked by the presence of multiple variants of these genes which increase risk for AMD. This rank will be used in risk factor models to more closely evaluate nutritional risk for AMD, considering possible enhanced power available after removing variation due to genetic susceptibility and controlling for potential confounding or effect modification of nutritional status to AMD conferred by variation in genetic susceptibility. These studies are expected to enhance our ability to develop practical public health recommendations that integrate the many aspects of diet which may slow the development of age-related macular degeneration. This evidence may also strengthen recommendations for modification of nutritional risk in people who have a family history for developing AMD.
The overall aim of these investigations is to determine the strength of nutritional factors on risk for AMD prevalence in persons with high and low genetic susceptibility for AMD, defined by common variants of genes associated with AMD risk and which may predict status of two key nutritional protective factors: blood 25 (OH) vitamin D and the macular density of the two carotenoids which comprise macular pigment, lutein and zeaxanthin.
Specifically, we will:
1) Use a high throughput platform to determine the presence of specific polymorphisms of the genes which have predicted AMD risk in other samples. These include single nucleotide polymorphisms on the following genes: CFH, ARMS2 and other complement factors genes CFI, C2, CFB and C3, APOE. We will also genotype for SNPS of genes which recent evidence suggests a role in the ability to accumulate macular pigment (ABCA1, GSTP1, SRB1) and vitamin D status and function (VDBP, CYP2R1, VDR, CYP27B1, CYP24A1) in women participating in the CAREDS sample for whom presence of AMD and other risk factors have been determined (n= 1,787).
2) Rank women by genetic risk, based on the joint presence of specific variants that increase risk of AMD in this and other samples.
3) Determine relationships of nutritional status to AMD among women with high and low genetic risk profile (defined as having ranks above and below the median). This includes:
A) Vitamin D status, defined by blood 25- OH vitamin D
B) Status of the retinal carotenoids, lutein and zeaxanthin, as defined by estimates of retinal tissue concentrations from existing estimates of macular pigment optical density.
C) Overall healthy diet patterns, reflecting high levels of several nutrients thought to be protective of AMD (lutein and zeaxanthin and vitamin E in diet and blood, beta-carotene, zinc, omega-three fatty acids and vitamin C in diets) and low levels of dietary fat, as estimated by score on a healthy eating index.