Amy E. Millen, Kristin J. Meyers, Zhe Liu, Corinne D. Engelman, Robert B. Wallace, Erin S. LeBlanc, Lesley F. Tinker, Sudha K. Iyengar, Jennifer G. Robinson, Gloria E. Sarto, Julie A. Mares

Deficient 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with increased odds of age-related macular degeneration (AMD). 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. 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. 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. 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. 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.