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Original Investigation |

Association Between Vitamin D Status and Age-Related Macular Degeneration by Genetic Risk

Amy E. Millen, PhD1; Kristin J. Meyers, PhD, MPH2; Zhe Liu, MS2; Corinne D. Engelman, PhD3; Robert B. Wallace, MD4; Erin S. LeBlanc, PhD5; Lesley F. Tinker, PhD6; Sudha K. Iyengar, PhD7; Jennifer G. Robinson, MD8; Gloria E. Sarto, MD, PhD9; Julie A. Mares, PhD2
[+] Author Affiliations
1Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo
2Department of Ophthalmology and Visual Sciences, The University of Wisconsin, Madison
3Department of Population Health Sciences, The University of Wisconsin, Madison
4Department of Epidemiology, The University of Iowa, Iowa City
5The Center for Health Research, Kaiser Permanente Research, Portland, Oregon
6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
7Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio
8Department of Epidemiology, University of Iowa College of Public Health, Iowa City
9Department of Obstetrics and Gynecology, School of Medicine & Public Health, University of Wisconsin, Madison
JAMA Ophthalmol. 2015;133(10):1171-1179. doi:10.1001/jamaophthalmol.2015.2715.
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Importance  Deficient 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with increased odds of age-related macular degeneration (AMD).

Objective  To examine whether this association is modified by genetic risk for AMD and whether there is an association between AMD and single-nucleotide polymorphisms of genes involved in vitamin D transport, metabolism, and genomic function.

Design, Setting, and Participants  Postmenopausal women (N = 913) who were participants of the Carotenoids in Age-Related Eye Disease Study (CAREDS) (aged 54 to <75 years) with available serum 25(OH)D concentrations (assessed October 1, 1993, to December 31, 1998), genetic data, and measures of AMD (n = 142) assessed at CAREDS baseline from May 14, 2001, through January 31, 2004, were studied.

Main Outcomes and Measures  Prevalent early or late AMD was determined from graded, stereoscopic fundus photographs. Logistic regression was used to estimate odds ratios (ORs) and 95% CIs for AMD by the joint effects of 25(OH)D (<12, ≥12 to <20, ≥20 to <30, and ≥30 ng/mL) and risk genotype (noncarrier, 1 risk allele, or 2 risk alleles). The referent group was noncarriers with adequate vitamin D status (≥30 ng/mL). Joint effect ORs were adjusted for age, smoking, iris pigmentation, self-reported cardiovascular disease, self-reported diabetes status, and hormone use. Additive and multiplicative interactions were assessed using the synergy index (SI) and an interaction term, respectively. To examine the association between AMD and variants in vitamin D–related genes, age-adjusted ORs and 95% CIs were estimated using logistic regression.

Results  Among the 913 women, 550 had adequate levels of vitamin D (≥20 ng/mL), 275 had inadequate levels (≥12 to <20 mg/mL), and 88 had deficient levels (<12 ng/mL). A 6.7-fold increased odds of AMD (95% CI, 1.6-28.2) was observed among women with deficient vitamin D status (25[OH]D <12 ng/mL) and 2 risk alleles for CFH Y402H (SI for additive interaction, 1.4; 95% CI, 1.1-1.7; P for multiplicative interaction = .25). Significant additive (SI, 1.4; 95% CI, 1.1-1.7) and multiplicative interactions (P = .02) were observed for deficient women with 2 high-risk CFI (rs10033900) alleles (OR, 6.3; 95% CI, 1.6-24.2). The odds of AMD did not differ by genotype of candidate vitamin D genes.

Conclusions and Relevance  In this study, the odds of AMD were highest in those with deficient vitamin D status and 2 risk alleles for the CFH and CFI genotypes, suggesting a synergistic effect between vitamin D status and complement cascade protein function. Limited sample size led to wide CIs. Findings may be due to chance or explained by residual confounding.

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