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1.  Dietary Omega-3 Fatty Acids, Other Fat Intake, Genetic Susceptibility and Progression to Incident Geographic Atrophy 
Ophthalmology  2013;120(5):1020-1028.
Objective
To investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD) and progression to geographic atrophy (GA).
Design
Observational analysis of a prospective cohort.
Participants
2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not.
Methods
Eyes without advanced AMD (GA or neovascular disease) at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements were collected at baseline using questionnaires. Dietary data was collected from food frequency questionnaires (FFQ) at baseline. Dietary fats, including omega-3 fatty acids (docosahexaenoic acid or DHA and eicosapentaenoic acid or EPA), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated and total fat were sex and calorie adjusted and divided into quintiles. Eight single nucleotide polymorphisms (SNPs) in 7 genes: CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, LIPC were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids, and interaction effects between dietary fat intake and genetic variation on risk of GA.
Main Outcome Measures
Associations between dietary fat intake reported from FFQs, genetic variants and incident GA.
Results
Increased intake of DHA was significantly associated with reduced risk of progression to GA in multivariate models with behavioral factors (Model A) and behavioral factors with genetic variants (Model B) (P-trend=0.008 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in Model B variants (P-trend =0.02). Monounsaturated fat was associated with increased risk in Model A (P=0.05).. DHA intake in the 5th quintile was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (HR = 0.4, P = 0.002, P – interaction between gene and fat intake = 0.05), whereas DHA was not associated with reduced risk of GA among those with the homozygous non-risk genotype (HR = 1.0, P= 0.90).
Conclusions
Increased self- reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA.
doi:10.1016/j.ophtha.2012.10.020
PMCID: PMC3758110  PMID: 23481534
2.  Risk Models for Progression to Advanced Age-Related Macular Degeneration Using Demographic, Environmental, Genetic, and Ocular Factors 
Ophthalmology  2011;118(11):2203-2211.
Purpose
To expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status.
Design
Prospective, longitudinal study.
Participants
We included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up.
Methods
Cox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables.
Main Outcome Measures
Progression to advanced AMD, including geographic atrophy and neovascular disease.
Results
In multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered.
Conclusions
Factors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references.
doi:10.1016/j.ophtha.2011.04.029
PMCID: PMC4097877  PMID: 21959373
3.  Genetic and Environmental Underpinnings to Age-Related Ocular Diseases 
Investigative Ophthalmology & Visual Science  2013;54(14):ORSF28-ORSF30.
Age-related macular degeneration (AMD), cataract, glaucoma and diabetic retinopathy are common causes of visual loss. Both environmental and genetic factors contribute to the development of these diseases. The modifiable factors related to some of these age-related and visually threatening diseases are smoking, obesity, and dietary factors, and a cardiovascular risk profile. Many common and a few rare genetic factors are associated with AMD. The role of genetic variants for the other diseases are less clear. Interactions between environmental, therapeutic, and genetic factors are being explored. Knowledge of genetic risk and environmental factors, especially for AMD, has grown markedly over the past 2.5 decades and has led to some sight-saving approaches in preventive management.
doi:10.1167/iovs.13-13234
PMCID: PMC3864375  PMID: 24335064
environment; genetics; age-related eye diseases; ORSF symposium
4.  Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes  
Ophthalmology  2012;119(9):1874-1885.
Purpose
To investigate whether the two subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV) and geographic atrophy (GA), segregate separately in families and to identify which genetic variants are associated with these two subtypes.
Design
Sibling correlation study and genome-wide association study (GWAS)
Participants
For the sibling correlation study, we included 209 sibling pairs with advanced AMD. For the GWAS, we included 2594 participants with advanced AMD subtypes and 4134 controls. Replication cohorts included 5383 advanced AMD participants and 15,240 controls.
Methods
Participants had AMD grade assigned based on fundus photography and/or examination. To determine heritability of advanced AMD subtypes, we performed a sibling correlation study. For the GWAS, we conducted genome-wide genotyping and imputed 6,036,699 single nucleotide polymorphism (SNPs). We then analyzed SNPs with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.
Main Outcome Measures
Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.
Results
The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P=4.2 x 10−5) meaning that siblings of probands with CNV or GA are more likely to develop CNV or GA, respectively. In the analysis comparing participants with CNV to those with GA, we observed a statistically significant association at the ARMS2/HTRA1 locus [rs10490924, odds ratio (OR)=1.47, P=4.3 ×10−9] which was confirmed in the replication samples (OR=1.38, P=7.4 x 10−14 for combined discovery and replication analysis).
Conclusions
Whether a patient with AMD develops CNV vs. GA is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations which differ for advanced AMD subtypes and deserve follow-up in additional studies.
doi:10.1016/j.ophtha.2012.03.014
PMCID: PMC3899891  PMID: 22705344
5.  Prediction Model for Prevalence and Incidence of Advanced Age-Related Macular Degeneration Based on Genetic, Demographic, and Environmental Variables 
Purpose
The joint effects of genetic, ocular, and environmental variables were evaluated and predictive models for prevalence and incidence of AMD were assessed.
Methods
Participants in the multicenter Age-Related Eye Disease Study (AREDS) were included in a prospective evaluation of 1446 individuals, of which 279 progressed to advanced AMD (geographic atrophy or neovascular disease) and 1167 did not progress during 6.3 years of follow-up. For prevalent AMD, 509 advanced cases were compared with 222 controls. Covariates for the incidence analysis included age, sex, education, smoking, body mass index (BMI), baseline AMD grade, and the AREDS vitamin–mineral treatment assignment. DNA specimens were evaluated for six variants in five genes related to AMD. Unconditional logistic regression analyses were performed for prevalent and incident advanced AMD. An algorithm was developed and receiver operating characteristic curves and C statistics were calculated to assess the predictive ability of risk scores to discriminate progressors from nonprogressors.
Results
All genetic polymorphisms were independently related to prevalence of advanced AMD, controlling for genetic factors, smoking, BMI, and AREDS treatment. Multivariate odds ratios (ORs) were 3.5 (95% confidence interval [CI], 1.7–7.1) for CFH Y402H; 3.7 (95% CI, 1.6 – 8.4) for CFH rs1410996; 25.4 (95% CI, 8.6 –75.1) for LOC387715 A69S (ARMS2); 0.3 (95% CI, 0.1– 0.7) for C2 E318D; 0.3 (95% CI, 0.1– 0.5) for CFB; and 3.6 (95% CI, 1.4 –9.4) for C3 R102G, comparing the homozygous risk/protective genotypes to the referent genotypes. For incident AMD, all these variants except CFB were significantly related to progression to advanced AMD, after controlling for baseline AMD grade and other factors, with ORs from 1.8 to 4.0 for presence of two risk alleles and 0.4 for the protective allele. An interaction was seen between CFH402H and treatment, after controlling for all genotypes. Smoking was independently related to AMD, with a multiplicative joint effect with genotype on AMD risk. The C statistic for the full model with all variables was 0.831 for progression to advanced AMD.
Conclusions
Factors reflective of nature and nurture are independently related to prevalence and incidence of advanced AMD, with excellent predictive power.
doi:10.1167/iovs.08-3064
PMCID: PMC3772781  PMID: 19117936
6.  ARMS2/HTRA1 Locus Can Confer Differential Susceptibility to the Advanced Subtypes of Age-Related Macular Degeneration 
American journal of ophthalmology  2010;151(2):345-52.e3.
Purpose
To determine if genetic variants that have been associated with age-related macular degeneration (AMD) have a differential effect on the risk of choroidal neovascularization (CNV) and geographic atrophy.
Design
Genetic association study.
Methods
Setting
Multicenter study.
Study Population
Seven hundred forty-nine participants with geographic atrophy and 3209 participants with CNV were derived from 4 AMD studies with similar procedures from Tufts Medical Center, the Age-Related Eye Disease Study, University of Utah, and Hopital Intercommunal de Creteil.
Procedures
AMD grade was assigned based on fundus photography and examination using the clinical age-related maculopathy staging system. All samples were genotyped for single nucleotide polymorphisms (SNPs) previously associated with AMD. Allele frequencies were compared between participants with CNV and geographic atrophy using PLINK within each cohort and Mantel-Haenszel meta-analysis was performed to combine odds ratios (OR).
Main Outcome Measures
Differences in allele frequencies between participants with geographic atrophy and CNV.
Results
The frequency of the T allele of ARMS2/HTRA1 rs10490924 was significantly higher in participants with CNV than in those with geographic atrophy (OR, 1.37; 95% confidence interval, 1.21–1.54; P value = 4.2 × 10−7). This result remained statistically significant when excluding individuals who had geographic atrophy in 1 eye and CNV in the contralateral eye (P = 2.2 × 10−4). None of the other SNPs showed a significant differential effect for CNV vs geographic atrophy, including CFH, C2/CFB, C3, CFI, LIPC, and TIMP3.
Conclusions
Genetic variation at the ARMS2/HTRA1 locus confers a differential risk for CNV vs geographic atrophy in a well-powered sample.
doi:10.1016/j.ajo.2010.08.015
PMCID: PMC3763907  PMID: 21122828
7.  C-Reactive Protein and CFH, ARMS2/HTRA1 Gene Variants Are Independently Associated with Risk of Macular Degeneration 
Ophthalmology  2010;117(8):1560-1566.
Purpose
Genetic variants CFH and ARMS2/HTRA1 gene regions as well as high-sensitivity C-reactive protein (CRP) levels are related to age-related macular degeneration (AMD). We evaluated their independent and combined effects on risk of AMD, as well as their interactions.
Design
Case-control study.
Participants
Subjects with AMD (n = 244) or no or minimal maculopathy (n = 209) in the Age Related Eye Disease Ancillary Study.
Methods
Risk factors, genotypes, and biomarkers were assessed by questionnaire, direct measurement, and analyses of blood specimens. The independent and joint effects of serum CRP and CFH (rs1061170) and ARMS2/HTRA1 (rs10490924) genotypes were assessed using logistic regression analyses, adjusting for age, gender, education, smoking, body mass index, and vitamin/mineral supplementation.
Main Outcome Measures
We defined AMD as large drusen, geographic atrophy, or neovascular disease.
Results
Higher CRP levels were associated with a higher risk of AMD, controlling for genotype and demographic and behavioral risk factors, with odds ratio 2.6 for levels of 3.0 mg/L and above versus below 1.0 mg/L (95% confidence interval, 1.01–6.7). Single nucleotide polymorphisms (SNPs) in both genes were also independently associated with risk of AMD, controlling for the level of CRP and other factors. Presence of both highest level of CRP together with risk genotypes for both SNPs, conferred the highest risk of AMD (OR 5.4, 95% CI 1.4–21.1).
Conclusions
High-sensitivity CRP and polymorphisms in the CFH and ARMS2/HTRA1 genes are independently associated with risk of AMD. Higher CRP level tends to confer a higher risk of AMD within most genotype groups.
doi:10.1016/j.ophtha.2009.11.020
PMCID: PMC3711558  PMID: 20346514
8.  Smoking, Dietary Betaine, Methionine, and Vitamin D in Monozygotic Twins with Discordant Macular Degeneration: Epigenetic Implications 
Ophthalmology  2011;118(7):1386-1394.
Objective
We evaluated monozygotic twin pairs with discordant age-related macular degeneration (AMD) phenotypes to assess differences in behavioral and nutritional factors.
Design
Case series.
Participants
Caucasian male twin pairs from the United States Twin Study of Macular Degeneration.
Methods
Twin pairs were genotyped to confirm monozygosity. Ocular characteristics were evaluated based on fundus photographs using the Wisconsin Grading System and a 5-grade Clinical Age-Related Maculopathy Staging System. We selected twin pairs discordant in each of the following phenotypic categories: Stage of AMD (n = 28), drusen area (n = 60), drusen size (n = 40), and increased pigment area (n = 56). The Wilcoxon signed-rank test and linear regression were used to assess associations between behavioral and nutritional characteristics and each phenotype within discordant twin pairs.
Main Outcome Measures
Differences in smoking and dietary factors within twin pairs discordant for stage of AMD, drusen area, drusen size, and pigment area.
Results
Representative fundus photographs depict the discordant phenotypes. Pack-years of smoking were higher for the twin with the more advanced stage of AMD (P = 0.05). Higher dietary intake of vitamin D was present in the twins with less severe AMD (P = 0.01) and smaller drusen size (P = 0.05) compared with co-twins, adjusted for smoking and age. Dietary intakes of betaine and methionine were significantly higher in the twin with lower stage of AMD (P = 0.009) and smaller drusen area (P = 0.03), respectively.
Conclusions
The twin with the more advanced stage of AMD, larger drusen area, drusen size, and pigment area tended to be the heavier smoker. The twin with the earlier stage of AMD, smaller drusen size and area, and less pigment tended to have higher dietary vitamin D, betaine, or methionine intake. Results suggest that behavioral and nutritional factors associated with epigenetic mechanisms are involved in the etiology of AMD, in addition to genetic susceptibility.
doi:10.1016/j.ophtha.2010.12.020
PMCID: PMC3711586  PMID: 21620475
9.  Cancer screening practices of adult survivors of retinoblastoma at risk of second cancers 
Cancer  2008;113(2):434-441.
Background
The aim of the current study was to investigate the pattern of cancer screening behavior in adult retinoblastoma survivors, who are at high risk of developing second cancers.
Methods
Self-reported cancer screening practices were investigated in a cohort of retinoblastoma survivors to evaluate whether they were receiving adequate screening for specific cancers and compare these rates with those of other adult survivors of childhood cancer and the general population. The prevalence of breast self-examination, clinical breast examination, mammography, Papanicolaou (Pap) test, testicular self-examination, and magnetic resonance imaging (MRI) or computed tomography (CT) scanning was determined from computer-aided telephone interviews with 836 retinoblastoma survivors aged >18 years.
Results
Among female survivors, 87% had a Pap test within the past 2 years, and 76% of females age >40 years reported having a mammogram within the past 2 years; 17.4% of male survivors had performed monthly testicular self-examinations. A significantly higher proportion of hereditary compared with nonhereditary survivors reported having undergone an MRI or CT scan in the past 5 years. Higher education, greater contact with the medical care system, and having a second cancer were found to be associated positively with most screening practices. Cancer screening practices reported by retinoblastoma survivors were similar to national screening rates for breast, cervical, and testicular cancer.
Conclusions
To the authors' knowledge, the current study provides the first report of cancer screening practices of retinoblastoma survivors. Survivors of hereditary retinoblastoma should be encouraged to maintain, if not increase, their current screening practices to ensure early detection of second cancers in this high-risk population.
doi:10.1002/cncr.23564
PMCID: PMC4012415  PMID: 18473349
10.  Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration 
Nature genetics  2013;45(11):1366-1370.
To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within AMD-associated loci and pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (OR=3.6, p=2×10−8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association to disease. We observed significant association with rare missense alleles outside CFI. Genotyping in 5,115 independent samples confirmed associations to AMD with a K155Q allele in C3 (replication p=3.5×10−5, OR=2.8; joint p=5.2×10−9, OR=3.8) and a P167S allele in C9 (replication p=2.4×10−5, OR=2.2; joint p=6.5×10−7, OR=2.2). Finally, we show that the 155Q allele in C3 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.
doi:10.1038/ng.2741
PMCID: PMC3902040  PMID: 24036952
11.  Genetic Factors for Choroidal Neovascularization Associated with High Myopia 
Purpose.
Nonsyndromic high myopia, defined by a refractive error greater than −6 diopters (D), is associated with an increased risk of macular choroidal neovascularization (CNV), a vision-threatening complication. The aim of this study was to investigate whether genetic factors associated with age-related macular degeneration (AMD) are related to myopic CNV.
Methods.
We conducted a case-control study, including 71 cases with myopic CNV and 196 myopic controls without CNV, from Creteil and Toulouse, France, and Boston, MA. Single nucleotide polymorphisms (SNPs) from 15 genes reported to be related to AMD were selected for association testing in this study.
Results.
In univariate analysis, the rs10033900 SNP located in CFI was associated with myopic CNV (P = 0.0011), and a SNP in APOE was also related (P = 0.041). After adjustment for age, sex, and degree of myopia, SNPs in three genes were significantly associated, including CFI (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.3–3.37, P = 0.0023), COL8A1 (OR 1.88, 95% CI 1.18–2.98, P = 0.0076), and CFH (OR 1.65, 95% CI 1.02–2.66, P = 0.04). After correction for multiple testing, only CFI remained significantly related to high myopic CNV (P = 0.045).
Conclusions.
We report the first genetic associations with choroidal neovascularization (CNV) in a high myopic Caucasian population. One SNP (rs10033900) in the CFI gene, which encodes a protein involved in the inflammatory pathway, was significantly associated with myopic CNV in multivariate analysis after correction for multiple testing. This SNP is a plausible biological marker associated with CNV outgrowth among high myopic patients. Results generate hypotheses about potential loci related to CNV in high myopia, and larger studies are needed to expand on these findings.
We report herein the first genetic associations with choroidal neovascularization (CNV) in a high myopic Caucasian population. One SNP in CFI was significantly associated with myopic CNV in multivariate analysis after correction for multiple testing.
doi:10.1167/iovs.12-9538
PMCID: PMC3410690  PMID: 22678500
12.  Prospective Assessment of Genetic Effects on Progression to Different Stages of Age-Related Macular Degeneration Using Multistate Markov Models 
Multistate Markov models were used to examine the effects of several candidate genes on progression from normal to intermediate stages and then to advanced stages of AMD in a large prospective study, controlling for baseline demographic and behavioral factors.
Purpose.
Understanding the effect of genes on progression to different stages of age-related macular degeneration (AMD) may suggest stage-specific therapeutic targets and more precise prediction of the development of this disease.
Methods.
Progression events and time to each stage of AMD were derived from the longitudinal data of 2560 subjects without advanced AMD. SNPs in 12 AMD risk loci were genotyped. A multistate Markov model for progression from normal to intermediate drusen, then to large drusen, and eventually to neovascular disease (NV) or geographic atrophy (GA) was applied to estimate stage-specific hazard ratios for each SNP. The effects of these genetic factors were also estimated by a multivariate multistate Markov model adjusted for baseline age, sex, smoking, body mass index (BMI), education, antioxidant treatment, and the status of AMD in the fellow eye.
Results.
Controlling for demographic and behavioral factors and other SNPs, the TT genotype of rs10468017 in LIPC was associated with decreased risk of progression from large drusen to NV (HR = 0.57, P = 0.04) and tended to reduce the risk of progression from normal to intermediate drusen (HR = 0.72, P = 0.07). The SNP rs1883025 (T allele) in ABCA1 was associated with decreased risk of progression from normal to intermediate drusen (HR per allele = 0.82 per allele, P = 9.7 × 10−3) and from intermediate drusen to large drusen (HR per allele = 0.77, P = 5.2 × 10−3). The genes CFH, C3, CFB, and ARMS2/HTRA1 were associated with progression from intermediate drusen to large drusen and from large drusen to GA or NV.
Conclusions.
Genes in different pathways influence progression to different stages of AMD.
doi:10.1167/iovs.11-8657
PMCID: PMC3339916  PMID: 22247473
13.  Three New Genetic Loci (R1210C in CFH, Variants in COL8A1 and RAD51B) Are Independently Related to Progression to Advanced Macular Degeneration 
PLoS ONE  2014;9(1):e87047.
Objectives
To assess the independent impact of new genetic variants on conversion to advanced stages of AMD, controlling for established risk factors, and to determine the contribution of genes in predictive models.
Methods
In this prospective longitudinal study of 2765 individuals, 777 subjects progressed to neovascular disease (NV) or geographic atrophy (GA) in either eye over 12 years. Recently reported genetic loci were assessed for their independent effects on incident advanced AMD after controlling for 6 established loci in 5 genes, and demographic, behavioral, and macular characteristics. New variants which remained significantly related to progression were then added to a final multivariate model to assess their independent effects. The contribution of genes to risk models was assessed using reclassification tables by determining risk within cross-classified quintiles for alternative models.
Results
Three new genetic variants were significantly related to progression: rare variant R1210C in CFH (hazard ratio (HR) 2.5, 95% confidence interval [CI] 1.2–5.3, P = 0.01), and common variants in genes COL8A1 (HR 2.0, 95% CI 1.1–3.5, P = 0.02) and RAD51B (HR 0.8, 95% CI 0.60–0.97, P = 0.03). The area under the curve statistic (AUC) was significantly higher for the 9 gene model (.884) vs the 0 gene model (.873), P = .01. AUC’s for the 9 vs 6 gene models were not significantly different, but reclassification analyses indicated significant added information for more genes, with adjusted odds ratios (OR) for progression within 5 years per one quintile increase in risk score of 2.7, P<0.001 for the 9 vs 6 loci model, and OR 3.5, P<0.001 for the 9 vs. 0 gene model. Similar results were seen for NV and GA.
Conclusions
Rare variant CFH R1210C and common variants in COL8A1 and RAD51B plus six genes in previous models contribute additional predictive information for advanced AMD beyond macular and behavioral phenotypes.
doi:10.1371/journal.pone.0087047
PMCID: PMC3909074  PMID: 24498017
14.  Association of Variants in the LIPC and ABCA1 Genes with Intermediate and Large Drusen and Advanced Age-Related Macular Degeneration 
HDL pathway genes LIPC and ABCA1 are associated with intermediate drusen, large drusen, and advanced AMD independent of age, sex, education, smoking, body mass index, antioxidant treatment, and other known genetic variants.
Purpose.
Intermediate and large drusen usually precede advanced age-related macular degeneration (AMD). There is little information about which genes influence drusen accumulation. Discovery of genetic variants associated with drusen may lead to prevention and treatments of AMD in its early stages.
Methods.
A total of 3066 subjects were evaluated on the basis of ocular examinations and fundus photography and categorized as control (n = 221), intermediate drusen (n = 814), large drusen (n = 949), or advanced AMD (n = 1082). SNPs in the previously identified CFH, C2, C3, CFB, CFI, APOE, and ARMS2/HTRA1 genes/regions and the novel genes LIPC, CETP, and ABCA1 in the high-density lipoprotein (HDL) cholesterol pathway were genotyped. Associations between stage of AMD and SNPs were assessed using logistic regression.
Results.
Controlling for age, sex, education, smoking, body mass index, and antioxidant treatment, the number of minor (T) alleles of the genes LIPC and ABCA1 were significantly associated with a reduced risk of intermediate drusen (LIPC [P trend = 0.045], ABCA1 [P = 4.4 × 10−3]), large drusen (LIPC [P = 0.041], ABCA1 [P = 7.7 × 10−4]), and advanced AMD (LIPC [P = 1.8 × 10−3], ABCA1 [P = 3 × 10−4]). After further adjustment for known genetic factors, the protective effect of the TT genotype was significant for intermediate drusen (LIPC [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.33–0.94], ABCA1 [OR, 0.48; 95% CI, 0.27–0.85]), large drusen (LIPC [OR, 0.58; 95% CI, 0.34–0.98)], ABCA1 [OR, 0.41; 95% CI, 0.23–0.74)]), and advanced AMD (LIPC [OR, 0.39; 95% CI, 0.21–0.74)], ABCA1 [OR, 0.35; 95% CI, 0.17–0.71)]). CFH, C3, C2, and ARMS2/HTRA1 were associated with large drusen and advanced AMD.
Conclusions.
LIPC and ABCA1 are related to intermediate and large drusen, as well as advanced AMD. CFH, C3, C2, and ARMS2/HTRA1 are associated with large drusen and advanced AMD. Genes may have varying effects on different stages of AMD.
doi:10.1167/iovs.10-7070
PMCID: PMC3175969  PMID: 21447678
15.  Genetic Profile for Five Common Variants Associated with Age-Related Macular Degeneration in Densely Affected Families: A Novel Analytic Approach 
About forty percent of the genetic variance of age-related macular degeneration can be explained by common variation at five common single nucleotide polymorphisms. We evaluated the degree to which these known variants explain the clustering of age-related macular degeneration in a group of densely affected families. We sought to determine if the actual number of risk alleles at the five variants in densely affected families matched the expected number. Using data from 322 families with age-related macular degeneration, we employed a simulation strategy to generate comparison groups of families and determined whether their genetic profile at the known age-related macular degeneration risk loci differed from the observed genetic profile, given the density of disease observed. Overall, the genotypic loads for the five single nucleotide polymorphisms in the families did not deviate significantly from the genotypic loads predicted by the simulation. However, for a subset of densely affected families, the mean genotypic load in the families was significantly lower than the expected load determined from the simulation. Given that these densely affected families may harbor rare, more penetrant variants for age-related macular degeneration, linkage analyses and resequencing targeting these families may be an effective approach to finding additional implicated genes.
doi:10.1038/ejhg.2009.185
PMCID: PMC2911949  PMID: 19844262
Age-related macular degeneration; complex trait; simulation; single nucleotide polymorphisms; liability threshold model
16.  Plasma Complement Components and Activation Fragments: Associations with Age-Related Macular Degeneration Genotypes and Phenotypes 
Purpose
Several genes encoding complement system components and fragments are associated with age-related macular degeneration (AMD). This study was conducted to determine whether alterations in circulating levels of these markers of complement activation and regulation are also independently associated with advanced AMD and whether they are related to AMD genotypes.
Methods
Plasma and DNA samples were selected from individuals in our AMD registry who had progressed to or developed the advanced stages of AMD, including 58 with geographic atrophy and 62 with neovascular disease. Subjects of similar age and sex, but without AMD, and who did not progress were included as controls (n = 60). Plasma complment components (C3, CFB, CFI, CFH, and factor D) and activation fragments (Bb, C3a, C5a, iC3b, and SC5b-9) were analyzed. DNA samples were genotyped for seven single-nucleotide polymorphisms in six genes previously shown to be associated with AMD: CFB, CFH, C2, C3, and CFI and the LOC387715/ARMS2 gene region. The association between AMD and each complement biomarker was assessed by using logistic regression, controlling for age, sex, and proinflammatory risk factors: smoking and body mass index (BMI). Functional genomic analyses were performed to assess the relationship between the complement markers and genotypes. Concordance, or C, statistics were calculated to assess the effect of complement components and activation fragments in an AMD gene-environment prediction model.
Results
The highest quartiles of Bb and C5a were significantly associated with advanced AMD, when compared with the lowest quartiles. In multivariate models without genetic variants, the odds ratio (OR) for Bb was 3.3 (95% confidence interval [CI] = 1.3-8.6), and the OR for C5a was 3.6 (95% CI = 1.2-10.3). With adjustment for genetic variants, these ORs were substantially higher. The alternative pathway regulator CFH was inversely associated with AMD in the model without genotypes (OR = 0.3; P = 0.01). Positive associations were found between BMI and plasma C3, CFB, CFH, iC3b, and C3a. There were also significant associations between C5a fragment and LOC387715/ARMS2 and C3 genotypes (P for trend = 0.02, 0.04), respectively. C statistics for models with behavioral and genetic factors increased to 0.94 ± 0.20 with the addition of C3a, Bb, and C5a.
Conclusions
Increased levels of activation fragments Bb and C5a are independently associated with AMD. Higher BMI is related to increased levels of complement components. C5a is associated with AMD genotypes. C statistics are stronger with the addition of C3a, Bb, and C5a in predictive models. Results implicate ongoing activation of the alternative complement pathway in AMD pathogenesis.
doi:10.1167/iovs.09-3928
PMCID: PMC2826794  PMID: 19661236
17.  The Relationship of Dietary ω-3 Long-Chain Polyunsaturated Fatty Acid Intake With Incident Age-Related Macular Degeneration AREDS Report No. 23 
Archives of ophthalmology  2008;126(9):1274-1279.
Objective
To examine the association of dietary ω-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA).
Methods
Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures.
Results
After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models.
Conclusions
Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary ω-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.
doi:10.1001/archopht.126.9.1274
PMCID: PMC2812063  PMID: 18779490
18.  Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration 
Molecular Vision  2010;16:2412-2424.
Objective
A novel locus in the hepatic lipase (LIPC) gene was found to be significantly related to advanced age-related macular degeneration (AMD) in our genome-wide association study. We evaluated its association and interaction with previously identified genetic variants and modifiable factors.
Methods
Participants in the Age-Related Eye Disease Study with advanced AMD (n=545 cases) or no AMD (n=275 controls) were evaluated. AMD status was determined using fundus photography. Covariates included cigarette smoking, body mass index (BMI), and dietary lutein. Individuals were genotyped for the rs10468017 polymorphism in LIPC as well as seven previously identified AMD genetic loci. Unconditional logistic regression analyses were then performed.
Results
The TT genotype of the LIPC variant was associated with a reduced risk of AMD, with odds ratios (OR) of 0.50 (95% confidence interval (CI) 0.20–0.90) and p=0.014 for the TT genotype versus the CC genotype, controlling for age, gender, smoking, body mass index (BMI), and nutritional factors. Controlling for seven other AMD genetic variants, the OR was 0.50, 95% (CI 0.20–1.1, p=0.077). The magnitude of the effect was similar for both atrophic and neovascular forms of AMD. Cigarette smoking and higher BMI increased the risk, while higher dietary lutein reduced the risk of advanced AMD, adjusting for genetic variants. There were no significant interactions between LIPC and smoking, BMI, or lutein. There was a possible association between LIPC and complement factor H (CFH) rs1410996, and a possible interaction effect between LIPC and both CFH rs10033900 and the complement factor I (CFI) variants in terms of risk of AMD.
Conclusions
LIPC is associated with reduced risk of advanced AMD, independent of demographic and environmental variables. Both genetic susceptibility and behavioral and lifestyle factors modify the risk of developing AMD.
PMCID: PMC2994762  PMID: 21139980
19.  A prospective study of diabetes, lifestyle factors, and glaucoma in African-American women 
Annals of epidemiology  2011;21(6):430-439.
PURPOSE
To evaluate the association of self-reported type 2 diabetes, anthropometric factors, alcohol consumption, and cigarette smoking with risk of primary open-angle glaucoma (POAG) in a prospective cohort study of African-American women.
METHODS
From 1995 through 2007, 32,570 Black Women’s Health Study participants aged 21–69 at baseline were followed for incident POAG. Questionnaires were mailed biennially to update exposures and identify incident cases of POAG. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were derived from Cox regression models.
RESULTS
During 416,171 person-years of follow-up, 366 incident POAG cases were confirmed by physician report. After adjustment for potential confounders, the IRR comparing women with and without type 2 diabetes was 1.58 (95%CI=1.17–2.13), and the IRR comparing current with never alcohol consumers was 1.35 (95% CI=1.05–1.73). Among women age <50 years, associations with diabetes and alcohol consumption were stronger, and POAG was significantly associated with BMI, waist circumference, waist-to-hip ratio, and both long-duration and high-intensity current smoking.
CONCLUSIONS
These results suggest that type 2 diabetes and current alcohol consumption are independent risk factors for POAG in African-American women, and that in addition to those factors, overall and central adiposity and smoking may be associated with increased risk of early-onset POAG
doi:10.1016/j.annepidem.2011.03.006
PMCID: PMC3091261  PMID: 21549278
african-americans; female; diabetes; anthropometry; smoking; alcohol; primary open-angle glaucoma
21.  Increased Risk of Secondary Uterine Leiomyosarcoma in Hereditary Retinoblastoma 
Gynecologic Oncology  2011;124(2):254-259.
Objective
In the US, second non-ocular malignancies are the primary cause of death in retinoblastoma survivors with the germline RB1 mutation. Soft tissue sarcomas are one of the most likely malignancies to pose a risk to these patients, with leiomyosarcoma (LMS) being the most common subtype. As our cohort is followed for a longer period, we discover new second malignancy risks for these patients.
Methods
We estimated the risk for uterine leiomyosarcoma (ULMS) in a cohort of 1854 patients with retinoblastoma who were diagnosed at two US institutions from 1914 through 1996. The standardized incidence ratio and excess absolute risk were calculated by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. The cumulative risk at 50 years of age was also calculated.
Results
Seven of 525 female hereditary retinoblastoma patients developed ULMS. Five of these patients were used in the risk analysis, resulting in an excess risk of 3.87 per 10,000 women. Among hereditary patients who developed ULMS the excess risk increases dramatically with age: to 20/10,000 for female hereditary retinoblastoma patients aged between 30–39 years, and to 27/10,000 for patients aged 40+ years.
Conclusion
There is a substantial excess risk of ULMS in female hereditary retinoblastoma patients. As more patients survive into their thirties, this number is likely to increase. These findings raise the question of early childbearing, screening and prophylactic measures in hereditary retinoblastoma patients: all issues that would benefit from confirmation from other retinoblastoma cohorts, to allow for better guided counsel of these patients.
doi:10.1016/j.ygyno.2011.10.019
PMCID: PMC3264733  PMID: 22027510
Retinoblastoma; Uterine Leiomyosarcoma; Secondary Cancers
23.  Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies 
Human mutation  2011;32(12):1407-1416.
Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status, has been reported. We present a pooled analysis (n=21,160) demonstrating associations between late AMD and APOε4 (OR=0.72 per haplotype; CI: 0.65–0.74; P=4.41×10−11) and APOε2 (OR=1.83 for homozygote carriers; CI: 1.04–3.23; P=0.04), following adjustment for age-group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR=1.54; CI: 1.38–1.72; P=2.8×10−15) and atrophic (OR=1.38; CI: 1.18–1.61; P=3.37×10−5) AMD but not early AMD (OR=0.94; CI: 0.86–1.03; P=0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyondε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
doi:10.1002/humu.21577
PMCID: PMC3217135  PMID: 21882290
age-related macular degeneration; AMD; apolipoprotein E; APOE; case-control association study
24.  Kidney function, albuminuria and age-related macular degeneration in NHANES III 
Nephrology Dialysis Transplantation  2011;26(10):3159-3165.
Background. Age-related macular degeneration (AMD) and kidney disease may have shared risk factors, including cardiovascular disease risk factors; additionally AMD and dense deposit disease share a common causal link, with both associated with polymorphisms in the complement pathway. Accordingly, we explored a population-based cohort of US adults to examine if markers of kidney disease identify a higher risk population for prevalent AMD.
Methods. A cross-sectional nested case–control study matching on age, sex and race was performed using data on adult participants in the Third National Health and Nutrition Examination Survey. Predictor variables included urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR). Study outcomes included late AMD, defined as neovascular disease or geographic atrophy (5:1 matching), and a composite of both early AMD, defined as soft drusen or pigment irregularities with or without any drusen, and late AMD (1:1 matching).
Results. There were 51 participants with late AMD and 865 with any AMD. In conditional logistic regression adjusting for diabetes, hypertension and total cholesterol, lower eGFR was independently associated with late AMD [odds ratio (OR) = 3.05, 95% confidence interval (CI): 1.51–6.13], while albuminuria was not significant. For any AMD, neither albuminuria nor eGFR were significant in adjusted models. In sensitivity analyses excluding diabetics, albuminuria was associated with any AMD (OR = 1.56, 95% CI: 1.11–1.29 and 1.57, 95% CI: 0.61–3.69 for micro- and macroalbuminuria, respectively, P = 0.03).
Conclusions. Late AMD is more common among individuals with reduced kidney function. Whether this association reflects a common causal pathway or shared risk factors such as hypertension requires additional investigation.
doi:10.1093/ndt/gfr022
PMCID: PMC3247860  PMID: 21339308
age-related macular degeneration; albuminuria; chronic kidney disease; dense deposit disease; glomerular filtration rate
25.  Variations in Apolipoprotein E Frequency With Age in a Pooled Analysis of a Large Group of Older People 
American Journal of Epidemiology  2011;173(12):1357-1364.
Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ2 for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ2 for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
doi:10.1093/aje/kwr015
PMCID: PMC3145394  PMID: 21498624
aged; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; apolipoproteins E; longevity; meta-analysis; multicenter study

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