Diet, Exercise, Smoking, and Genes Interact in AMD Risk

Ricki Lewis, PhD

September 21, 2015

Lifestyle factors and genetic susceptibility can interact synergistically to elevate the risk for age-related macular degeneration (AMD) in women, according to two new analyses of the Carotenoids in Age-Related Eye Disease Study (CAREDS). The analyses were published online September 6 in Ophthalmology and published online on August 27 in JAMA Ophthalmology.

"A large body of scientific evidence indicates that healthy lifestyle modifications can lower processes thought to promote AMD, including oxidative stress, inflammation, blood lipoprotein disturbances, and hypertension," Kristin J. Meyers, PhD, from the Department of Ophthalmology and Visual Sciences, McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, and colleagues write in Ophthalmology.

But "[g]enetic risk may modify the benefit of a healthy lifestyle," they explain.

In their study, Dr Meyers and colleagues assessed a trio of lifestyle habits — Healthy Eating Index scores, physical activity level, and smoking pack-years — among 1663 women aged 50 to 79 years in the CAREDS cohort.

The researchers then considered whether the participants had one, two, or no copies of the Y402H allele of the complement factor H (CFH) gene and of the A69S allele of the age-related maculopathy susceptibility locus 2 (ARMS2) gene, both of which are known to elevate risk for early and late AMD in Europeans.

The main outcome was AMD diagnosis and severity, determined using stereoscopic fundus photographs taken in 2001 to 2004, 6 years after the lifestyle assessments. AMD affected 337 women, 91% of whom had early disease.

The investigators computed a synergy index (SI) to determine whether the increase in AMD risk from genetic contribution and poor lifestyle exceeded the sum of the individual risks, which would suggest both risk factors intervene in the same process, such as the inflammatory response. Another hypothesis is that genetic risk factors multiply AMD risks in the presence of unhealthy lifestyles, which would support the value of genetic testing to identify high-risk individuals.

The study also evaluated levels of lutein and zeaxanthin (LZ; carotenoid pigments that shield the macula from blue wavelengths and lower oxidative stress and inflammation) in the diet, blood, or retina. Diet and genetics are both known to influence LZ levels.

The odds of AMD were 3.30 times greater (95% confidence interval [CI], 1.80 - 6.05) among women with a low healthy lifestyle score (0 - 2) and two high-risk CFH alleles relative to participants who had high healthy lifestyle scores (4 - 6) and two low-risk CFH alleles.

The joint effect of lifestyle score and CFH genotype equaled the sum of their individual effects (SI, 1.08; 95% CI, 0.70 - 1.67), indicating no synergy; nor was there evidence for multiplicative interaction. Synergy became apparent, however, when the researchers considered only the 728 women who had stable diets before the AMD assessment, discounting participants whose fluctuating dietary LZ levels might have biased conclusions. Limiting the sample strengthened the odds for association of AMD with low healthy lifestyle scores and high-risk CFH genotype (odds ratio, 4.63; 95% CI, 1.85 - 11.60). The joint effect in the restricted group was significant (SI, 1.34; 95% CI, 1.05 - 1.70), suggesting synergy. ARMS2 genotype was not associated with additive or multiplicative interactions with lifestyle in AMD risk.

The researchers conclude that inheriting 2 CFH high-risk alleles can worsen the effects of an unhealthy lifestyle on AMD risk for postmenopausal women with a stable diet, but caution that because the lifestyle factor is important for any genotype, "genotyping to identify persons at high risk may not be clinically necessary."

In the study reported in JAMA Ophthalmology, from the same multi-institution research group, Amy E. Millen, PhD, from the Department of Epidemiology and Environmental Health at the University at Buffalo, and colleagues probed the relationship between vitamin D deficiency and variants of genes associated with increased risk for AMD.

The team assessed AMD status among 913 women from CAREDS, which had previously associated elevated AMD risk with low levels of vitamin D. The investigators analyzed whether the vitamin D–associated risk was elevated among women who had certain alleles of genes that influence inflammatory pathways or vitamin D transport or metabolism.

Women were subgrouped by whether they had one, two, or no copies of each gene variant and by whether vitamin D intake was adequate, inadequate, or deficient. The results indicate an association of vitamin D deficiency with two genes that encode complement proteins, but not with genes involved in the transport or metabolism of vitamin D.

Among the 913 participants, 550 had adequate levels of vitamin D (at least 20 ng/mL), 275 had inadequate levels (≥12 to <20 ng/mL), and 88 had deficient levels (<12 ng/mL). Women with deficient vitamin D and two high-risk alleles for CFH (Y402H) had a 6.7-fold increased odds of AMD (95% CI, 1.6 - 28.2) compared with a 1.8-fold increase among women with inadequate vitamin D and no CFH risk alleles.

Having two variants of the CFI gene, which encodes complement factor I, was associated with a 6.3-fold increased odds of AMD (95% CI, 1.6 - 24.2).

The researchers conclude that the highest risk is among women who are vitamin D deficient and have two high-risk alleles for either CFH or CFI. Genotypes of candidate vitamin D genes did not affect AMD risk.

Limitations of both studies were the restriction of the sample to well-educated white women and taking the ocular photographs 6 years after assessments of lifestyle factors and vitamin D status.

The authors have disclosed no relevant financial relationships.

Ophthalmol. Published online September 6, 2015. Abstract

JAMA Ophthalmol. Published online August 27, 2015. Abstract

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