Vitamin D intake and season modify the effects of the GC and CYP2R1 genes on 25-hydroxyvitamin D concentrations.

Vitamin D deficiency {defined by the blood concentration of 25-hydroxyvitamin D [25(OH)D]} has been associated with many adverse health outcomes. Genetic and nongenetic factors account for variation in 25(OH)D, but the role of interactions between these factors is unknown. To assess this, we examined 1204 women of European descent from the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative Observational Study. Twenty-nine single nucleotide polymorphisms (SNPs) in 4 genes, GC, CYP2R1, DHCR7, and CYP24A1, from recent meta-analyses of 25(OH)D genome-wide association studies were genotyped. Associations between these SNPs and 25(OH)D were tested using generalized linear regression under an additive genetic model adjusted for age, blood draw month, and ancestry. Results were stratified by season of blood draw and, separately, vitamin D intake for the 6 SNPs showing a significant association with 25(OH)D at the P < 0.01 level. Two nonsynonymous SNPs in GC and 4 SNPs in CYP2R1 were strongly associated with 25(OH)D in individuals whose blood was drawn in summer (P ≤ 0.002) but not winter months and, independently, in individuals with vitamin D intakes ≥400 (P ≤ 0.004) but not <400 IU/d (10 µg/d). This effect modification, if confirmed, has important implications for the design of genetic studies for all health outcomes and for public health recommendations and clinical practice guidelines regarding the achievement of adequate vitamin D status.

Genetic evidence for role of carotenoids in age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS).

PURPOSE: We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS). METHODS: Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid-related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0-4.9). CONCLUSIONS: Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD.

Genetic determinants of macular pigments in women of the Carotenoids in Age-Related Eye Disease Study.

PURPOSE: To investigate genetic determinants of macular pigment optical density in women from the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women's Health Initiative Observational Study. METHODS: 1585 of 2005 CAREDS participants had macular pigment optical density (MPOD) measured noninvasively using customized heterochromatic flicker photometry and blood samples genotyped for 440 single nucleotide polymorphisms (SNPs) in 26 candidate genes related to absorption, transport, binding, and cleavage of carotenoids directly, or via lipid transport. SNPs were individually tested for associations with MPOD using least-squares linear regression. RESULTS: Twenty-one SNPs from 11 genes were associated with MPOD (P ≤ 0.05) after adjusting for dietary intake of lutein and zeaxanthin. This includes variants in or near genes related to zeaxanthin binding in the macula (GSTP1), carotenoid cleavage (BCMO1), cholesterol transport or uptake (SCARB1, ABCA1, ABCG5, and LIPC), long-chain omega-3 fatty acid status (ELOVL2, FADS1, and FADS2), and various maculopathies (ALDH3A2 and RPE65). The strongest association was for rs11645428 near BCMO1 (ßA = 0.029, P = 2.2 × 10(-4)). Conditional modeling within genes and further adjustment for other predictors of MPOD, including waist circumference, diabetes, and dietary intake of fiber, resulted in 13 SNPs from 10 genes maintaining independent association with MPOD. Variation in these single gene polymorphisms accounted for 5% of the variability in MPOD (P = 3.5 × 10(-11)). CONCLUSIONS: Our results support that MPOD is a multi-factorial phenotype associated with variation in genes related to carotenoid transport, uptake, and metabolism, independent of known dietary and health influences on MPOD.