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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.  Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans: The Candidate Gene Association Resource (CARe) Study 
Background
Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study.
Methods and Results
Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10−07). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43 × 10−07) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 × 10−07) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 × 10−08) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 × 10−07) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN.
Conclusions
In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
doi:10.1161/CIRCGENETICS.111.962365
PMCID: PMC3591479  PMID: 23275298
echocardiography; ethnic; genome-wide association studies; Left atrium genetics; left ventricular mass genetics
4.  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
5.  Genetic variation in NCAM1 contributes to left ventricular wall thickness in hypertensive families 
Circulation Research  2011;108(3):279-283.
Rationale
Left ventricular (LV) mass and related phenotypes are heritable, important predictors of cardiovascular disease, particularly in hypertensive individuals.
Objective
Identify genetic predictors of echocardiographic phenotypes in hypertensive families.
Methods & Results
A multi-stage genome-wide association study (GWAS) was conducted in hypertensive-ascertained African American families (HyperGEN, Stage I; GENOA, Stage II); findings were replicated in HyperGEN Caucasian families (Stage III). Echocardiograms were collected using a common protocol, and participants were genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. In Stages I and II, 1258 and 989 African Americans, and Stage III 1316 Caucasians, were analyzed using mixed models adjusted for ancestry. Phenotypes included LV mass, LV internal dimension (LVID), wall thicknesses (posterior (PWT) and intraventricular septum (IVST)), and relative wall thickness (RWT). In Stage I, 5 single nucleotide polymorphisms (SNP) had P≤10−6. In Stage II, one SNP (rs1436109; NCAM1 intron 1) replicated with the same phenotype (PWT, P=0.025) in addition to RWT (P=0.032). In Stage III, rs1436109 was associated with RWT (P=5.47×10−4) and LVID (P=1.86×10−4). Fisher’s combined P-value for all stages was RWT=3.80×10−9, PWT=3.12×10−7, IVST=8.69×10−7, LV mass=2.52×10−3, and LVID=4.80×10−4.
Conclusions
This GWAS conducted in hypertensive families identified a variant in NCAM1 associated with LV wall thickness and RWT. NCAM is upregulated during the remodeling period of hypertrophy to heart failure in Dahl salt-sensitive rats. Our initial screening in hypertensive African-Americans may have provided the context for this novel locus.
doi:10.1161/CIRCRESAHA.110.239210
PMCID: PMC3328104  PMID: 21212386
GWAS; NCAM1; hypertrophy; genomics
6.  Analysis of human mini-exome sequencing data from Genetic Analysis Workshop 17 using a Bayesian hierarchical mixture model 
BMC Proceedings  2011;5(Suppl 9):S93.
Next-generation sequencing technologies are rapidly changing the field of genetic epidemiology and enabling exploration of the full allele frequency spectrum underlying complex diseases. Although sequencing technologies have shifted our focus toward rare genetic variants, statistical methods traditionally used in genetic association studies are inadequate for estimating effects of low minor allele frequency variants. Four our study we use the Genetic Analysis Workshop 17 data from 697 unrelated individuals (genotypes for 24,487 autosomal variants from 3,205 genes). We apply a Bayesian hierarchical mixture model to identify genes associated with a simulated binary phenotype using a transformed genotype design matrix weighted by allele frequencies. A Metropolis Hasting algorithm is used to jointly sample each indicator variable and additive genetic effect pair from its conditional posterior distribution, and remaining parameters are sampled by Gibbs sampling. This method identified 58 genes with a posterior probability greater than 0.8 for being associated with the phenotype. One of these 58 genes, PIK3C2B was correctly identified as being associated with affected status based on the simulation process. This project demonstrates the utility of Bayesian hierarchical mixture models using a transformed genotype matrix to detect genes containing rare and common variants associated with a binary phenotype.
doi:10.1186/1753-6561-5-S9-S93
PMCID: PMC3287935  PMID: 22373180
7.  Genome-wide association study of vitamin D concentrations in Hispanic Americans: The IRAS Family Study 
Vitamin D deficiency is associated with many adverse health outcomes. There are several well established environmental predictors of vitamin D concentrations, yet studies of the genetic determinants of vitamin D concentrations are in their infancy. Our objective was to conduct a pilot genome-wide association (GWA) study of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations in a subset of 229 Hispanic subjects, followed by replication genotyping of 50 single nucleotide polymorphisms (SNPs) in the entire sample of 1,190 Hispanics from San Antonio, Texas and San Luis Valley, Colorado. Of the 309,200 SNPs that met all quality control criteria, three SNPs in high linkage disequilibrium (LD) with each other were significantly associated with 1,25[OH]2D (rs6680429, rs9970802, and rs10889028) at a Bonferroni corrected P-value threshold of 1.62 × 10−7, however none met the threshold for 25[OH]D. Of the 50 SNPs selected for replication genotyping, five for 25[OH]D (rs2806508, rs10141935, rs4778359, rs1507023, and rs9937918) and eight for 1,25[OH]2D (rs6680429, rs1348864, rs4559029, rs12667374, rs7781309, rs10505337, rs2486443, and rs2154175) were replicated in the entire sample of Hispanics (P < 0.01). In conclusion, we identified several SNPs that were associated with vitamin D metabolite concentrations in Hispanics. These candidate polymorphisms merit further investigation in independent populations and other ethnicities.
doi:10.1016/j.jsbmb.2010.06.013
PMCID: PMC2949505  PMID: 20600896
Vitamin D; 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; genome-wide association study; Hispanic
8.  Genome-wide joint SNP and CNV analysis of aortic root diameter in African Americans: the HyperGEN study 
Background
Aortic root diameter is a clinically relevant trait due to its known relationship with the pathogenesis of aortic regurgitation and risk for aortic dissection. African Americans are an understudied population despite a particularly high burden of cardiovascular diseases. We report a genome-wide association study on aortic root diameter among African Americans enrolled in the HyperGEN study. We invoked a two-stage, mixed model procedure to jointly identify SNP allele and copy number variation effects.
Results
Results suggest novel genetic contributors along a large region between the CRCP and KCTD7 genes on chromosome 7 (p = 4.26 × 10-7); and the SIRPA and PDYN genes on chromosome 20 (p = 3.28 × 10-8).
Conclusions
The regions we discovered are candidates for future studies on cardiovascular outcomes, particularly in African Americans. The methods we employed can also provide an outline for genetic researchers interested in jointly testing SNP and CNV effects and/or applying mixed model procedures on a genome-wide scale.
doi:10.1186/1755-8794-4-4
PMCID: PMC3027088  PMID: 21223598
9.  SNP-SNP interactions dominate the genetic architecture of candidate genes associated with left ventricular mass in african-americans of the GENOA study 
BMC Medical Genetics  2010;11:160.
Background
Left ventricular mass (LVM) is a strong, independent predictor of heart disease incidence and mortality. LVM is a complex, quantitative trait with genetic and environmental risk factors. This research characterizes the genetic architecture of LVM in an African-American population by examining the main and interactive effects of individual candidate gene single nucleotide polymorphisms (SNPs) and conventional risk factors for increased LVM.
Methods
We used least-squares linear regression to investigate 1,878 SNPs from 234 candidate genes for SNP main effects, SNP-risk factor interactions, or SNP-SNP interactions associated with LVM in 1,328 African-Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We reduced the probability of false positive results by implementing three analytic criteria: 1) the false discovery rate, 2) cross-validation, and 3) testing for internal replication of results.
Results
We identified 409 SNP-SNP interactions passing all three criteria, while no SNP main effects or SNP-risk factor interactions passed all three. A multivariable model including four SNP-SNP interactions explained 11.3% of the variation in LVM in the full GENOA sample and 5.6% of LVM variation in independent test sets.
Conclusions
The results of this research underscore that context dependent effects, specifically SNP-SNP interactions, may dominate genetic contributions to variation in complex traits such as LVM.
doi:10.1186/1471-2350-11-160
PMCID: PMC2991303  PMID: 21067599
10.  Detecting gene-by-smoking interactions in a genome-wide association study of early-onset coronary heart disease using random forests 
BMC Proceedings  2009;3(Suppl 7):S88.
Background
Genome-wide association studies are often limited in their ability to attain their full potential due to the sheer volume of information created. We sought to use the random forest algorithm to identify single-nucleotide polymorphisms (SNPs) that may be involved in gene-by-smoking interactions related to the early-onset of coronary heart disease.
Methods
Using data from the Framingham Heart Study, our analysis used a case-only design in which the outcome of interest was age of onset of early coronary heart disease.
Results
Smoking status was dichotomized as ever versus never. The single SNP with the highest importance score assigned by random forests was rs2011345. This SNP was not associated with age alone in the control subjects. Using generalized estimating equations to adjust for sex and account for familial correlation, there was evidence of an interaction between rs2011345 and smoking status.
Conclusion
The results of this analysis suggest that random forests may be a useful tool for identifying SNPs taking part in gene-by-environment interactions in genome-wide association studies.
PMCID: PMC2795991  PMID: 20018084

Results 1-10 (10)