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Johanna M. Seddon - One of the best experts on this subject based on the ideXlab platform.
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association between perifoveal drusen burden determined by oct and genetic risk in early and intermediate age related macular degeneration
Investigative Ophthalmology & Visual Science, 2019Co-Authors: Johanna M. Seddon, James Dossett, Rafael Widjajahakim, Bernard RosnerAbstract:Purpose The purpose of this study was to determine associations between macular drusen parameters derived from an automatic optical coherence tomography (OCT) algorithm, nonadvanced age-related macular degeneration (AMD) stage, and genetic variants. Methods Eyes classified as early or intermediate AMD with OCT imaging and genetic data were selected (n = 239 eyes). Drusen area and volume measurements were estimated using the Zeiss Cirrus advanced retinal pigment epithelium analysis algorithm in a perifoveal zone centered on the fovea. Associations between drusen measurements and common genetic variants in the complement and high-density lipoprotein (HDL) lipid pathways and the ARMS2/HTRA1 variant were calculated using generalized estimating equations and linear mixed models adjusting for age, sex, smoking, body mass index, and education. Results Drusen area ≥ the median was independently associated with a higher number of risk alleles for CFH risk score and risk variants in C3 and ARMS2/HTRA1 compared with eyes with no measurable drusen. Similar results were obtained for drusen volume. When all genes were analyzed in the same model, only CFH score and ARMS2/HTRA1 were associated with drusen measurements. HDL pathway genes were not significantly related to drusen parameters. Nonadvanced AMD stages were associated with OCT-derived drusen area and volume. Conclusions Variants in CFH and ARMS2/HTRA1, commonly associated with advanced AMD, were independently associated with an increase in drusen burden determined by OCT in an allele dose dependent manner, in eyes with early and intermediate AMD. Biomarkers such as a quantitative classification of nonadvanced AMD and other OCT-derived subphenotypes could provide earlier anatomic endpoints for clinical trials and facilitate the development of new therapies for AMD.
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association between drusen burden determined by oct and genetic risk in early and intermediate age related macular degeneration
bioRxiv, 2019Co-Authors: Johanna M. Seddon, James Dossett, Rafael Widjajahakim, Bernard RosnerAbstract:ABSTRACT PURPOSE To determine associations between macular drusen parameters derived from an automatic optical coherence tomography (OCT) algorithm, age-related macular degeneration (AMD) stage and genetic variants. METHODS Eyes classified as early or intermediate AMD with OCT imaging and genetic data were selected (n=239 eyes). Drusen area and volume measurements were estimated using the Zeiss Cirrus advanced retinal pigment epithelium (RPE) analysis algorithm in a 5mm diameter (perifoveal) zone centered on the fovea. Associations between drusen measurements and common genetic variants in the complement and high density lipoprotein (HDL) lipid pathways and the ARMS2 variant were calculated using generalized estimating equations and linear mixed models adjusting for age, sex, smoking, BMI, and education. RESULTS When compared to eyes with no measurable drusen, drusen area ≥ the median was independently associated with a higher number of risk alleles for CFH risk score, risk variants in C3 and ARMS2/HTRA1. Similar results were obtained for drusen volume. When all genes were analyzed in the same model, only CFH score and ARMS2/HTRA1 were associated with drusen measurements. HDL pathway genes were not significantly related to drusen parameters. Early and intermediate AMD stages were associated with OCT derived drusen area and volume. CONCLUSION Genetic variants in CFH and ARMS2/HTRA1, commonly associated with advanced AMD, were independently associated with higher drusen burden determined by OCT in eyes with early and intermediate AMD. The automatic RPE algorithm using OCT provides a quantitative classification of non-advanced AMD. Drusen morphology and other OCT-derived sub-phenotypes are biomarkers that could provide early anatomic endpoints for clinical trials.
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response to areds supplements according to genetic factors survival analysis approach using the eye as the unit of analysis
British Journal of Ophthalmology, 2016Co-Authors: Johanna M. Seddon, Rachel E Silver, Bernard RosnerAbstract:Background/aims The Age-Related Eye Disease Study (AREDS) reported the beneficial impact of antioxidant and zinc supplements on the risk of progression to advanced stages of age-related macular degeneration (AMD). We evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD. Methods Among 4124 eyes (2317 subjects with a genetic specimen), 882 progressed from no AMD, early or intermediate AMD to overall advanced disease, including geographic atrophy (GA) and neovascular disease (NV) over the course of the clinical trial. Survival analysis using individual eyes as the unit of analysis was used to assess the effect of supplementation on AMD outcomes, with adjustment for demographic, environmental, ocular and genetic covariates. Interaction effects between supplement groups and individual complement factor H (CFH) Y402H and age-related maculopathy susceptibility 2 ( ARMS2 ) genotypes, and composite genetic risk groups combining the number of risk alleles for both loci, were evaluated for their association with progression. Results Among antioxidant and zinc supplement users compared with the placebo group, subjects with a non-risk genotype for CFH (TT) had a lower risk of progression to advanced AMD (HR: 0.55, 95% CI 0.32 to 0.95, p=0.033). No significant treatment effect was apparent among subjects who were homozygous for the CFH risk allele (CC). A protective effect was observed among high-risk ARMS2 (TT) carriers (HR: 0.52, 95% CI 0.33 to 0.82, p=0.005). Similar results were seen for the NV subtype but not GA. Conclusions The effectiveness of antioxidant and zinc supplementation appears to differ by genotype. Further study is needed to determine the biological basis for this interaction. Trial registration number NCT00594672, pre-results.
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dietary omega 3 fatty acids other fat intake genetic susceptibility and progression to incident geographic atrophy
Ophthalmology, 2013Co-Authors: Robyn Reynolds, Johanna M. Seddon, Bernard RosnerAbstract: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 A total of 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 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 were collected from food frequency questionnaires (FFQs) at baseline. Omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated, and total fat were adjusted for sex and calories and divided into quintiles (Q). Eight single nucleotide polymorphisms in 7 genes ( CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, and 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 models with behavioral factors (model A) plus genetic variants (model B) ( P trend=0.01 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 ( P trend=0.02). Monounsaturated fat was associated with increased risk in model A ( P trend=0.05). DHA intake was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (hazard ratio [HR] Q5 vs Q1, 0.4; P = 0.002; P for interaction between gene and fat intake=0.05). DHA was not associated with reduced risk of GA among those with the homozygous ARMS2/HTRA1 nonrisk 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. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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rs5888 variant of SCARB1 gene is a possible susceptibility factor for age-related macular degeneration
PLoS ONE, 2009Co-Authors: Jennyfer Zerbib, Johanna M. Seddon, Florence Richard, Robyn Reynolds, Nicolas Leveziel, Pascale Benlian, Patrick Borel, Josué Feingold, Arnold Munnich, Gisele SoubraneAbstract:Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors, including variants in the CFH gene and the ARMS2 LOC387715/HTRA1locus. Our purpose was to perform a case-control study in two populations among individuals who did not carry risk variants for CFHY402H and LOC387715 A69S (ARMS2), called ‘‘study’’ individuals, in order to identify new genetic risk factors. Based on a candidate gene approach, we analyzed SNP rs5888 of the SCARB1 gene, coding for SRBI, which is involved in the lipid and lutein pathways. This study was conducted in a French series of 1241 AMD patients and 297 controls, and in a North American series of 1257 patients with advanced AMD and 1732 controls. Among these individuals, we identified 61 French patients, 77 French controls, 85 North American patients and 338 North American controls who did not carry the CFH nor ARMS2 polymorphisms. An association between AMD and the SCARB1 gene was seen among the study subjects. The genotypic distribution of the rs5888 polymorphism was significantly different between cases and controls in the French population (p,0.006). Heterozygosity at the rs5888 SNP increased risk of AMD compared to the CC genotypes in the French study population (odds ratio (OR) = 3.5, CI95%: 1.4–8.9, p,0.01) and after pooling the 2 populations (OR = 2.9, 95% CI: 1.6–5.3, p,0.002). Subgroup analysis in exudative forms of AMD revealed a pooled OR of 3.6 for individuals heterozygous for rs5888 (95% CI: 1.7–7.6, p,0.0015). These results suggest the possible contribution of SCARB1, a new genetic factor in AMD, and implicate a role for cholesterol and antioxidant micronutrient (lutein and vitamin E) metabolism in AMD
Brian Kaderli - One of the best experts on this subject based on the ideXlab platform.
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association between high risk disease loci and response to anti vascular endothelial growth factor treatment for wet age related macular degeneration
Retina-the Journal of Retinal and Vitreous Diseases, 2012Co-Authors: Anton Orlin, Dexter Hadley, Gary C Brown, Carl D Regillo, Brian Kaderli, Woohyok Chang, Richard S Kaiser, Ashlee N Godshalk, Audun Lier, Dwight StambolianAbstract:Purpose:To investigate whether there is an association between known age-related macular degeneration genetic risk variants in the CFH, ARMS2, and HTRA1 genes and response to anti–vascular endothelial growth factor (VEGF) (ranibizumab or bevacizumab) treatment for wet age-related macular degeneratio
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analysis of six genetic risk factors highly associated with amd in the region surrounding ARMS2 and htra1 on chromosome 10 region q26
Investigative Ophthalmology & Visual Science, 2010Co-Authors: Dexter Hadley, Anton Orlin, Gary C Brown, Alexander J Brucker, Carl D Regillo, Larry A Donoso, Lifeng Tian, Brian KaderliAbstract:Purpose. To determine the relationship of six genetic variants (rs10490924, rs3750848, del443ins54, rs3793917, rs11200638, and rs932275) localized to the ARMS2-HTRA1 region of chromosome 10, region q26, as risk factors for age-related macular degeneration (AMD), to define the haplotype structure of these six loci, and to confirm their genetic association with the disease. Methods. Caucasian patients (n = 482) were stratified into categories based on AREDS (Age-Related Eye Disease Study) grading criteria (groups 0 and 1 served as the control, groups 3 and 4 contained subjects with AMD, and group 2 was excluded from the analysis). The six genetic variants in the ARMS2-HTRA1 region were genotyped and analyzed both independently and as a joint haplotype for association in subjects with disease (n = 291) compared with the control (n = 191). Results. The six high-risk alleles all showed a statistically significant association with AMD (the most significant SNP was rs10490924 [P 98% of the genetic variation in the region were both significantly associated with the disease: One increased the risk of AMD and contained only risk alleles (P < or = 2.20 x 10(-5)), and the other haplotype decreased the risk of AMD and contained only wild-type alleles (P < or = 6.81 x 10(-5)). Furthermore, 36 individuals comprising both cases and controls were identified outside of these two major haplotypes, with at least one discordant marker. Conclusions. The results replicate the previously reported association between the high-risk alleles and AMD and independently confirm, for the first time, an association with AMD and the indel (del443ins54) polymorphism in a Caucasian population. Two major haplotypes that are associated with AMD and many minor novel haplotypes were identified. The novel haplotypes, identified from 36 cases and controls with discordant alleles spanning the ARMS2-HTRA1 region provide unique opportunities to gauge the relative phenotypic contributions of each of these genetic risk factors. With the identification of more discordant patients in the future, it may be possible to resolve the ongoing controversy as to which of the risk alleles and genes (ARMS2 vs. HTRA1) has the greatest impact on disease susceptibility. Future work should include the analysis of larger and more diverse populations, to further define the linkage structure of the region with a focus on phenotypic effects on AMD of the various haplotypes involving 10q26, as well as a functional analysis of the normal ARMS2 protein.
Dwight Stambolian - One of the best experts on this subject based on the ideXlab platform.
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association between high risk disease loci and response to anti vascular endothelial growth factor treatment for wet age related macular degeneration
Retina-the Journal of Retinal and Vitreous Diseases, 2012Co-Authors: Anton Orlin, Dexter Hadley, Gary C Brown, Carl D Regillo, Brian Kaderli, Woohyok Chang, Richard S Kaiser, Ashlee N Godshalk, Audun Lier, Dwight StambolianAbstract:Purpose:To investigate whether there is an association between known age-related macular degeneration genetic risk variants in the CFH, ARMS2, and HTRA1 genes and response to anti–vascular endothelial growth factor (VEGF) (ranibizumab or bevacizumab) treatment for wet age-related macular degeneratio
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age related macular degeneration associated variants at chromosome 10q26 do not significantly alter ARMS2 and htra1 transcript levels in the human retina
Molecular Vision, 2010Co-Authors: Atsuhiro Kanda, Dwight Stambolian, Wei Chen, Christine A Curcio, Goncalo R Abecasis, Anand SwaroopAbstract:PURPOSE Multiple studies demonstrate a strong association between three variants at chromosome 10q26 - rs10490924, del443ins54, and rs11200638 - near the age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement factor A1 (HTRA1) genes with susceptibility to age-related macular degeneration (AMD). In different reports, the del443ins54 and rs11200638 variants are suggested to affect ARMS2 mRNA stability and/or HTRA1 mRNA expression, respectively. The goal of this study is to examine whether these AMD-associated variants alter expression levels of ARMS2 and HTRA1 in human retina samples. METHODS Genomic DNA and total RNA were obtained from 35 human retinas (three young controls, average age=32 years; twenty aged controls, average age=72 years; and twelve AMD retinas, average age=77 years) using standard procedures. As ARMS2 exhibits higher expression in the human placenta, we also included eighteen placenta samples in our analysis. Four polymorphisms - rs2736911, rs10490924, del443ins54, and rs11200638 - were genotyped by PCR followed by sequencing. Expression of ARMS2, HTRA1 and three endogenous control genes (rRNA [rRNA], hypoxanthine phosphoribosyltransferase 1 [HPRT1], and glyceraldehyde-3-phosphate dehydrogenase [GAPDH]) was measured by real-time quantitative RT-PCR using Taqman gene expression or SYBR Green assays. RESULTS ARMS2 and HTRA1 mRNA levels did not show a significant difference in expression among the control (young and elderly) and AMD retinas. No association of del443ins54 and rs11200638 variants was detected with mRNA expression levels of ARMS2 or HTRA1 in the retina. Human placenta samples showed high variability in expression levels. CONCLUSIONS We did not find association between AMD susceptibility variants at 10q26 and steady-state expression levels of either ARMS2 or HTRA1 in the human retina.
Emily Y Chew - One of the best experts on this subject based on the ideXlab platform.
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no cfh or ARMS2 interaction with omega 3 fatty acids low versus high zinc or β carotene versus lutein and zeaxanthin on progression of age related macular degeneration in the age related eye disease study 2 age related eye disease study 2 report no 18
Ophthalmology, 2019Co-Authors: Freekje Van Asten, Anand Swaroop, Chiyang Chiu, Elvira Agron, Traci E Clemons, Rinki Ratnapriya, Michael L Klein, Ruzong Fan, Emily Y ChewAbstract:Purpose To assess whether genotypes at 2 major loci associated with age-related macular degeneration (AMD), complement factor H (CFH), or age-related maculopathy susceptibility 2 (ARMS2), modify the response to oral nutrients for the treatment of AMD in the Age-Related Eye Disease Study 2 (AREDS2). Design Post hoc analysis of a randomized trial. Participants White AREDS2 participants. Methods AREDS2 participants (n = 4203) with bilateral large drusen or late AMD in 1 eye were assigned randomly to lutein and zeaxanthin, omega-3 fatty acids, both, or placebo, and most also received the AREDS supplements. A secondary randomization assessed modified AREDS supplements in 4 treatment arms: lower zinc dosage, omission of β-carotene, both, or no modification. To evaluate the progression to late AMD, fundus photographs were obtained at baseline and annual study visits, and history of treatment for late AMD was obtained at study visits and 6-month interim telephone calls. Participants were genotyped for the single-nucleotide polymorphisms rs1061170 in CFH and rs10490924 in ARMS2. Bivariate frailty models using both eyes were conducted, including a gene–supplement interaction term and adjusting for age, gender, level of education, and smoking status. The main treatment effects, as well as the direct comparison between lutein plus zeaxanthin and β-carotene, were assessed for genotype interaction. Main Outcome Measures The interaction between genotype and the response to AREDS2 supplements regarding progression to late AMD, any geographic atrophy (GA), and neovascular AMD. Results Complete data were available for 2775 eyes without baseline late AMD (1684 participants). The participants (mean age ± standard deviation, 72.1±7.7 years; 58.5% female) were followed up for a median of 5 years. The ARMS2 risk allele was associated significantly with progression to late AMD and neovascular AMD (P = 2.40 × 10–5 and P = 0.002, respectively), but not any GA (P = 0.097). The CFH risk allele was not associated with AMD progression. Genotype did not modify significantly the response to any of the AREDS2 supplements. Conclusions CFH and ARMS2 risk alleles do not modify the response to the AREDS2 nutrient supplements with respect to the progression to late AMD (GA and neovascular AMD).
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progression of geographic atrophy and genotype in age related macular degeneration
Ophthalmology, 2010Co-Authors: Michael L Klein, Emily Y Chew, Frederick L Ferris, Peter J Francis, Anne S Lindblad, Sara C HamonAbstract:Purpose We sought to determine whether genotype is associated with rate of growth of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). Design Prospective analysis of participants in a randomized controlled clinical trial. Participants We included 114 eyes of 114 participants in the Age-Related Eye Disease Study (AREDS). Methods Fundus photographs from AREDS participants with GA from whom a DNA specimen had been obtained and serial photographs had been taken over a minimum of 2 years were evaluated for progression as determined by change in cumulative area of GA. All fundus photographs were scanned, digitized, and centrally graded longitudinally for area of GA. The relationship of GA progression with previously identified genetic variants associated with AMD was assessed. Main Outcome Measures Genotype frequencies and change in cumulative area of GA. Results The mean growth rate of GA for the 114 eyes was 1.79 mm 2 /year (range, 0.17–4.76). No association between growth rate and genotype was present for variants in the CFH , C2 , C3 , APOE , and TLR3 genes. For the single nucleotide polymorphism rs10490924 in LOC387715/ARMS2 , there was a significant association of GA growth rate, both adjusted and unadjusted for initial lesion size, with the homozygous risk genotype as compared with the homozygous nonrisk genotype (unadjusted P = 0.002; Bonferroni-corrected P = 0.014) and for allelic association (Bonferroni-corrected P value=0.011). Analyses of other measures of GA progression (progression to central GA from extrafoveal GA and development of bilateral GA in those initially with unilateral GA) showed no statistically significant association between progression and the LOC387715/ARMS2/HTRA1 genotype. Conclusions Growth rates of GA calculated from digitized serial fundus photographs showed no association with variants in the CFH , C2 , C3 , APOE , or TLR3 genes. There was a nominally significant association with the LOC387715/ARMS2/HTRA1 genotype, although this finding was not supported by analyses of secondary measures of GA progression. Replication in other populations is needed to establish the existence of an association. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Michael L Klein - One of the best experts on this subject based on the ideXlab platform.
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no cfh or ARMS2 interaction with omega 3 fatty acids low versus high zinc or β carotene versus lutein and zeaxanthin on progression of age related macular degeneration in the age related eye disease study 2 age related eye disease study 2 report no 18
Ophthalmology, 2019Co-Authors: Freekje Van Asten, Anand Swaroop, Chiyang Chiu, Elvira Agron, Traci E Clemons, Rinki Ratnapriya, Michael L Klein, Ruzong Fan, Emily Y ChewAbstract:Purpose To assess whether genotypes at 2 major loci associated with age-related macular degeneration (AMD), complement factor H (CFH), or age-related maculopathy susceptibility 2 (ARMS2), modify the response to oral nutrients for the treatment of AMD in the Age-Related Eye Disease Study 2 (AREDS2). Design Post hoc analysis of a randomized trial. Participants White AREDS2 participants. Methods AREDS2 participants (n = 4203) with bilateral large drusen or late AMD in 1 eye were assigned randomly to lutein and zeaxanthin, omega-3 fatty acids, both, or placebo, and most also received the AREDS supplements. A secondary randomization assessed modified AREDS supplements in 4 treatment arms: lower zinc dosage, omission of β-carotene, both, or no modification. To evaluate the progression to late AMD, fundus photographs were obtained at baseline and annual study visits, and history of treatment for late AMD was obtained at study visits and 6-month interim telephone calls. Participants were genotyped for the single-nucleotide polymorphisms rs1061170 in CFH and rs10490924 in ARMS2. Bivariate frailty models using both eyes were conducted, including a gene–supplement interaction term and adjusting for age, gender, level of education, and smoking status. The main treatment effects, as well as the direct comparison between lutein plus zeaxanthin and β-carotene, were assessed for genotype interaction. Main Outcome Measures The interaction between genotype and the response to AREDS2 supplements regarding progression to late AMD, any geographic atrophy (GA), and neovascular AMD. Results Complete data were available for 2775 eyes without baseline late AMD (1684 participants). The participants (mean age ± standard deviation, 72.1±7.7 years; 58.5% female) were followed up for a median of 5 years. The ARMS2 risk allele was associated significantly with progression to late AMD and neovascular AMD (P = 2.40 × 10–5 and P = 0.002, respectively), but not any GA (P = 0.097). The CFH risk allele was not associated with AMD progression. Genotype did not modify significantly the response to any of the AREDS2 supplements. Conclusions CFH and ARMS2 risk alleles do not modify the response to the AREDS2 nutrient supplements with respect to the progression to late AMD (GA and neovascular AMD).
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joint associations of diet lifestyle and genes with age related macular degeneration
Ophthalmology, 2015Co-Authors: Kristin J Meyers, Michael L Klein, Sudha K Iyengar, Zhe Liu, Amy E Millen, Barbara A Blodi, Elizabeth J Johnson, Max D Snodderly, Karen M Gehrs, Lesley F TinkerAbstract:Purpose Unhealthy lifestyles have been associated with increased odds for age-related macular degeneration (AMD). Whether this association is modified by genetic risk for AMD is unknown and was investigated. Design Interactions between healthy lifestyles AMD risk genotypes were studied in relation to the prevalence of AMD, assessed 6 years later. Participants Women 50 to 79 years of age in the Carotenoids in Age-Related Eye Disease Study with exposure and AMD data (n = 1663). Methods Healthy lifestyle scores (0–6 points) were assigned based on Healthy Eating Index scores, physical activity (metabolic equivalent of task hours/week), and smoking pack years assessed in 1994 and 1998. Genetic risk was based on Y402H in complement factor H ( CFH ) and A69S in age-related maculopathy susceptibility locus 2 ( ARMS2 ). Additive and multiplicative interactions in odds ratios were assessed using the synergy index and a multiplicative interaction term, respectively. Main Outcome Measures AMD presence and severity were assessed from grading of stereoscopic fundus photographs taken in 2001–2004. AMD was present in 337 women, 91% of whom had early AMD. Results The odds of AMD were 3.3 times greater (95% confidence interval [CI], 1.8-6.1) in women with both low healthy lifestyle score (0–2) and high-risk CFH genotype (CC), relative to those who had low genetic risk (TT) and high healthy lifestyle scores (4–6). There were no significant additive (synergy index [SI], 1.08; 95% CI, 0.70–1.67) or multiplicative ( P interaction = 0.94) interactions in the full sample. However, when limiting the sample to women with stable diets before AMD assessment (n = 728) the odds for AMD associated with low healthy lifestyle scores and high-risk CFH genotype were strengthened (odds ratio, 4.6; 95% CI, 1.8–11.6) and the synergy index was significant (SI, 1.34; 95% CI, 1.05–1.70). Adjusting for dietary lutein and zeaxanthin attenuated, and therefore partially explained, the joint association. There were no significant additive or multiplicative interactions for ARMS2 and lifestyle score. Conclusions Having unhealthy lifestyles and 2 CFH risk alleles increased AMD risk (primarily in the early stages), in an or additive or greater (synergistic) manner. However, unhealthy lifestyles increased AMD risk regardless of AMD risk genotype.
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pharmacogenetics for genes associated with age related macular degeneration in the comparison of amd treatments trials catt
Ophthalmology, 2013Co-Authors: Michael L Klein, Stephanie A Hagstrom, Guishuang Ying, Gayle J T Pauer, Gwen M Sturgillshort, Jiayan Huang, David Callanan, Ivana K Kim, Maureen G MaguireAbstract:Purpose To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech) for neovascular AMD. Design Clinical trial. Participants Eight hundred thirty-four (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers. Methods Each patient was genotyped for SNPs rs1061170 ( CFH ), rs10490924 ( ARMS2 ), rs11200638 ( HTRA1 ), and rs2230199 ( C3 ), using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA). Main Outcomes Measures Genotypic frequencies were compared with clinical measures of response to therapy at one year, including mean visual acuity (VA), mean change in VA, 15-letter or more increase in VA, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, P ≤0.01 was considered statistically significant. Results No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomic response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size), or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; that is, response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata dosing. Conclusions Although specific alleles for CFH, ARMS2, HTRA1, and C3 may predict the development of AMD, they did not predict response to anti–vascular endothelial growth factor therapy. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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progression of geographic atrophy and genotype in age related macular degeneration
Ophthalmology, 2010Co-Authors: Michael L Klein, Emily Y Chew, Frederick L Ferris, Peter J Francis, Anne S Lindblad, Sara C HamonAbstract:Purpose We sought to determine whether genotype is associated with rate of growth of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). Design Prospective analysis of participants in a randomized controlled clinical trial. Participants We included 114 eyes of 114 participants in the Age-Related Eye Disease Study (AREDS). Methods Fundus photographs from AREDS participants with GA from whom a DNA specimen had been obtained and serial photographs had been taken over a minimum of 2 years were evaluated for progression as determined by change in cumulative area of GA. All fundus photographs were scanned, digitized, and centrally graded longitudinally for area of GA. The relationship of GA progression with previously identified genetic variants associated with AMD was assessed. Main Outcome Measures Genotype frequencies and change in cumulative area of GA. Results The mean growth rate of GA for the 114 eyes was 1.79 mm 2 /year (range, 0.17–4.76). No association between growth rate and genotype was present for variants in the CFH , C2 , C3 , APOE , and TLR3 genes. For the single nucleotide polymorphism rs10490924 in LOC387715/ARMS2 , there was a significant association of GA growth rate, both adjusted and unadjusted for initial lesion size, with the homozygous risk genotype as compared with the homozygous nonrisk genotype (unadjusted P = 0.002; Bonferroni-corrected P = 0.014) and for allelic association (Bonferroni-corrected P value=0.011). Analyses of other measures of GA progression (progression to central GA from extrafoveal GA and development of bilateral GA in those initially with unilateral GA) showed no statistically significant association between progression and the LOC387715/ARMS2/HTRA1 genotype. Conclusions Growth rates of GA calculated from digitized serial fundus photographs showed no association with variants in the CFH , C2 , C3 , APOE , or TLR3 genes. There was a nominally significant association with the LOC387715/ARMS2/HTRA1 genotype, although this finding was not supported by analyses of secondary measures of GA progression. Replication in other populations is needed to establish the existence of an association. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.