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1.  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.
In this study of over 1600 postmenopausal women of the CAREDS, we describe the first evidence that variation in multiple genes related to carotenoid status in the blood and macula are associated with age-related macular degeneration (AMD).
doi:10.1167/iovs.13-13216
PMCID: PMC3908680  PMID: 24346170
macular degeneration; carotenoids; genes
2.  Investigation of genetic variation in scavenger receptor class B, member 1 (SCARB1) and association with serum carotenoids 
Ophthalmology  2013;120(8):1632-1640.
Objective
To investigate association of scavenger receptor class B, member 1 (SCARB1) genetic variants with serum carotenoid levels of lutein (L) and zeaxanthin (Z) and macular pigment optical density (MPOD).
Design
A cross-sectional study of healthy adults aged 20-70.
Participants
302 participants recruited following local advertisement.
Methods
MPOD was measured by customized heterochromatic flicker photometry. Fasting blood samples were taken for serum L and Z measurement by HPLC and lipoprotein analysis by spectrophotometric assay. Forty-seven single nucleotide polymorphisms (SNPs) across SCARB1 were genotyped using Sequenom technology. Association analyses were performed using PLINK to compare allele and haplotype means, with adjustment for potential confounding and correction for multiple comparisons by permutation testing. Replication analysis was performed in the TwinsUK and CAREDS cohorts.
Main outcome measures
Odds ratios (ORs) for macular pigment optical density area, serum lutein and zeaxanthin concentrations associated with genetic variations in SCARB1 and interactions between SCARB1 and sex.
Results
Following multiple regression analysis with adjustment for age, body mass index, sex, high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides, smoking, dietary L and Z levels, 5 SNPs were significantly associated with serum L concentration and 1 SNP with MPOD (P<0.01). Only the association between rs11057841 and serum L withstood correction for multiple comparisons by permutation testing (P<0.01) and replicated in the TwinsUK cohort (P=0.014). Independent replication was also observed in the CAREDS cohort with rs10846744 (P=2×10−4), a SNP in high linkage disequilibrium with rs11057841 (r2=0.93). No significant interactions by sex were found. Haplotype analysis revealed no stronger association than obtained with single SNP analyses.
Conclusions
Our study has identified association between rs11057841 and serum L concentration (24% increase per T allele) in healthy subjects, independent of potential confounding factors. Our data supports further evaluation of the role for SCARB1 in the transport of macular pigment and the possible modulation of AMD risk through combating the effects of oxidative stress within the retina.
doi:10.1016/j.ophtha.2013.01.030
PMCID: PMC3946979  PMID: 23562302
Age-related macular degeneration; association study; lutein; macular pigment; macular pigment optical density; SCARB1; zeaxanthin
3.  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 (βA = 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.
In 1585 postmenopausal women of the Carotenoids in Age-Related Eye Disease Study sample, common genetic variants in or near genes involved in carotenoid transport, uptake, and metabolism were associated with density of lutein and zeaxanthin in the macula, independent of other known predictors, including dietary intake of carotenoids.
doi:10.1167/iovs.12-10867
PMCID: PMC3626525  PMID: 23404124
4.  Using Regression Calibration Equations That Combine Self-Reported Intake and Biomarker Measures to Obtain Unbiased Estimates and More Powerful Tests of Dietary Associations 
American Journal of Epidemiology  2011;174(11):1238-1245.
The authors describe a statistical method of combining self-reports and biomarkers that, with adequate control for confounding, will provide nearly unbiased estimates of diet-disease associations and a valid test of the null hypothesis of no association. The method is based on regression calibration. In cases in which the diet-disease association is mediated by the biomarker, the association needs to be estimated as the total dietary effect in a mediation model. However, the hypothesis of no association is best tested through a marginal model that includes as the exposure the regression calibration-estimated intake but not the biomarker. The authors illustrate the method with data from the Carotenoids and Age-Related Eye Disease Study (2001--2004) and show that inclusion of the biomarker in the regression calibration-estimated intake increases the statistical power. This development sheds light on previous analyses of diet-disease associations reported in the literature.
doi:10.1093/aje/kwr248
PMCID: PMC3224252  PMID: 22047826
bias (epidemiology); carotenoids; cataract; lutein; measurement error; sample size
5.  Duration of Physical Activity and Serum 25-hydroxyvitamin D Status of Postmenopausal Women 
Annals of epidemiology  2011;21(6):440-449.
Purpose
To investigate whether the association between physical activity and serum 25-hydroxyvitamin D (25(OH)D) concentrations is independent of sun exposure, body size, and other potential explanatory variables.
Methods
Using data from a sample of 1,343 postmenopausal women, from the Women’s Health Initiative, linear regression was used to examine the associations of duration (minutes/week) of recreational activity and of yard work with 25(OH)D concentrations (nmol/L).
Results
In age-adjusted analyses, positive associations were observed between 25(OH)D concentrations and both duration of recreational physical activity (β=0.71, SE(0.09), P<0.001) and yard work (β=0.36, SE(0.10), P=0.004). After further adjustment for vitamin D intake, self-reported sunlight exposure, waist circumference, and season of blood draw, 25(OH)D was significantly associated with recreational activity (β=0.21, SE(0.09), P=0.014) but not with yard work (β=0.18, SE(0.09), P=0.061). Interactions were observed between season and both recreational activity (Pinteraction=0.082) and yard work (Pinteraction=0.038) such that these activity-25(OH)D associations were greater during summer/fall compared to winter/spring. Self-reported sunlight exposure and measures of body size did not modify the associations.
Conclusion
The observed age-adjusted activity-25(OH)D associations were attenuated after adjusting for explanatory variables and were modified by season of blood draw. Adopting a lifestyle that incorporates outdoor physical activity during summer/fall, consuming recommended amounts of vitamin D, and maintaining a healthy weight may improve or maintain vitamin D status in postmenopausal women.
doi:10.1016/j.annepidem.2010.11.011
PMCID: PMC3090482  PMID: 21414803
25-hydroxyvitamin D; vitamin D; serum; sunlight exposure; physical activity; epidemiology; women
6.  Association between dietary fats and age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women’s Health Initiative123 
Archives of ophthalmology  2009;127(11):1483-1493.
Objective
Evaluating relationships of amount and type of dietary fat to intermediate AMD.
Design
Women, ages 50–79, from the Women’s Health Initiative-Observational Study, with high and low lutein intakes, were recruited into the Carotenoids in Age-Related Eye Disease Study (CAREDS). Fat intake in 1994–1998 was estimated using food frequency questionnaires. AMD was assessed in 2001–2004 from stereoscopic fundus photographs.
Results
Intakes of omega-6 and omega-3 polyunsaturated fats (ω-6 and ω-3 PUFA), which were highly correlated (r=0.8), were associated with higher prevalence of intermediate AMD. Significant age-interactions were noted for associations with total fat, monounsaturated and saturated fat (p= 0.01–0.02). In women <75 years (n=1,325), diets high in total fat (% energy) were associated with increased prevalence of AMD (OR (95% CI) for quintile five vs. one = 1.73 (1.02–2.7; p-trend=0.10); the association was reversed in older women. Monounsaturated fat (MUFA) intakes in quintiles three through five vs. one were associated with lower prevalence of AMD in the whole population.
Conclusions
Overall associations of dietary fat to AMD differed by type of fat and, often, by age in this cohort. These findings contribute insights about sources of inconsistencies of fat to AMD in epidemiological studies.
doi:10.1001/archophthalmol.2009.130
PMCID: PMC3144752  PMID: 19901214
total fat; saturated fats; omega-6 polyunsaturated fats; monounsaturated fats; omega-3 polyunsaturated fats; age-related macular degeneration
7.  Healthy Diets and the Subsequent Prevalence of Nuclear Cataract in Women 
Archives of ophthalmology  2010;128(6):738-749.
Objective and Design
The association between healthy diet scores which reflect adherence to the US Dietary Guidelines and prevalence of nuclear cataract, assessed four to seven years later, was assessed in a sample of Women's Health Initiative (WHI) Observational Study participants (50–79 years of age) who were residing in Iowa, Wisconsin and Oregon. Scores on the 1995 Healthy Eating Index (HEI-95), which reflect adherence to 1990 guidelines, were assigned from responses to food frequency questionnaires at WHI-baseline (1994–1998). Presence of nuclear cataract was determined from slit-lamp photographs and self-report of cataract extractions were assessed from 2001–04 in the Carotenoids in Age-Related Eye Disease Study (N=1,808).
Results
Having a high HEI-95 score was the strongest modifiable predictor of low prevalence of nuclear cataract among numerous risk factors investigated in this sample. The multivariable-adjusted OR and 95% confidence interval for high vs. low quintile for diet score were 0.6 (0.4–0.9). Higher prevalence of nuclear cataract was also associated with other modifiable factors (smoking and marked obesity) and non-modifiable factors (having brown eyes, myopia and high pulse pressure). Vitamin supplement use was not related to cataract.
Conclusion
These data add to the body of evidence suggesting that eating foods that are rich in a variety of vitamins and minerals, may contribute to postponing the occurrence of the most common type of cataract in the US.
doi:10.1001/archophthalmol.2010.84
PMCID: PMC2896219  PMID: 20547952
8.  Vitamin D Status and Early Age-Related Macular Degeneration in Postmenopausal Women 
Archives of ophthalmology  2011;129(4):481-489.
Objective
The relationship between serum 25-hydroxyvitamin D (25(OH)D) concentrations (nmol/L) and the prevalence of early age-related macular degeneration (AMD) was investigated among participants of the Carotenoids in Age-Related Eye Disease Study.
Methods
Stereoscopic fundus photographs, taken from 2001–2004, assessed AMD status. Baseline (1994–1998) serum samples were available for 25(OH)D assays in 1,313 women with complete ocular and risk factor data. Odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD (n=241), among 1,287 without advanced disease, were estimated with logistic regression and adjusted for age, smoking, iris pigmentation, family history of AMD, cardiovascular disease, diabetes, and hormone therapy use.
Results
In multivariate models, no significant relationship was observed between early AMD and 25(OH)D (OR for quintile 5 vs. 1=0.79, 95% CI=0.50–1.24; p for trend=0.47). A significant age interaction (p=0.0025) suggested selective mortality bias in women ≥75 years: serum 25(OH)D was associated with decreased odds of early AMD in women <75 years (n=968) and increased odds in women ≥75 years (n=319) (OR for quintile 5 vs. 1=0.52, 95% CI=0.29–0.91; p for trend=0.02 and 1.76, 95% CI=0.77–4.13; p for trend=0.05, respectively). Further adjustment for body mass index and recreational physical activity, predictors of 25(OH)D, attenuated the observed association in women <75 years. Additionally, among women <75 years, intake of vitamin D from foods and supplements was related to decreased odds of early AMD in multivariate models; no relationship was observed with self-reported time spent in direct sunlight.
Conclusions
High serum 25(OH)D concentrations may protect against early AMD in women <75 years.
doi:10.1001/archophthalmol.2011.48
PMCID: PMC3075411  PMID: 21482873
vitamin D; 25-hydroxyvitamin D; sunlight; diet; macular degeneration; cohort studies; epidemiology
9.  Gains in Statistical Power From Using a Dietary Biomarker in Combination With Self-reported Intake to Strengthen the Analysis of a Diet-Disease Association: An Example From CAREDS 
American Journal of Epidemiology  2010;172(7):836-842.
A major problem in detecting diet-disease associations in nutritional cohort studies is measurement error in self-reported intakes, which causes loss of statistical power. The authors propose using biomarkers correlated with dietary intake to strengthen analyses of diet-disease hypotheses and to increase statistical power. They consider combining self-reported intakes and biomarker levels using principal components or a sum of ranks and relating the combined measure to disease in conventional regression analyses. They illustrate their method in a study of the inverse association of dietary lutein plus zeaxanthin with nuclear cataracts, using serum lutein plus zeaxanthin as the biomarker, with data from the Carotenoids in Age-Related Eye Disease Study (United States, 2001–2004). This example demonstrates that the combined measure provides higher statistical significance than the dietary measure or the serum measure alone, and it potentially provides sample savings of 8%–53% over analysis with dietary intake alone and of 6%–48% over analysis with serum level alone, depending on the definition of the outcome variable and the choice of confounders entered into the regression model. The authors conclude that combining appropriate biomarkers with dietary data in a cohort can strengthen the investigation of diet-disease associations by increasing the statistical power to detect them.
doi:10.1093/aje/kwq194
PMCID: PMC2945826  PMID: 20716705
carotenoids; cataract; lutein; ranks; sample size
10.  Associations between age-related nuclear cataract and lutein and zeaxanthin in the diet and serum in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women's Health Initiative 
Archives of ophthalmology  2008;126(3):354-364.
Objective and Design:
Women aged 50-79 years in Iowa, Wisconsin, and Oregon with intakes of lutein and zeaxanthin (L+Z) above the 78th (high) and below the 28th (low) percentiles in the Women's Health Initiative Observational Study (1994-98) were recruited four to seven years later (2001-04) into the Carotenoids in Age-Related Eye Disease Study (CAREDS) to evaluate associations between nuclear cataract (determined from slit-lamp photographs) and L+Z in the diet and serum in 1994-98 and macula in 2001-04 (N=1,802).
Results:
Women in the high dietary L+Z group had a 23% lower prevalence of nuclear cataract (age-adjusted odds ratio [OR]: 0.77, 95% confidence interval [CI]: 0.62-0.96) compared to those in the low group. Multivariable adjustment slightly attenuated the association (OR (95% CI): 0.81 (0.65-1.01)). Women in the highest vs. lowest quintile categories of diet or serum L+Z were 32% less likely to have nuclear cataract (multivariable-adjusted OR (95% CI): 0.68 (0.48-0.97), p trend=0.04 and 0.68 (0.47-0.98), p trend=0.01). Cross-sectional associations with macular pigment density were inverse but not statistically significant.
Conclusion:
Diets rich in lutein and zeaxanthin are moderately associated with decreased prevalence of nuclear cataract in older women. However, other protective aspects of such diets may, in part, explain these relationships.
doi:10.1001/archopht.126.3.354
PMCID: PMC2562026  PMID: 18332316

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