Risk Of AMD Research Articles

Ophthalmic ophthalmology

SummaryHow Do Patients Respond to Genetic Testing for AMD?The goal of this project was to conduct a pilot AMD genomic medicine study. Eligible patients aged 50‐65 with no personal AMD history gave informed consent and DNA samples were genotyped for 5 single nucleotide polymorphisms (SNPs) in the CFH gene, 1 SNP in the ARMS‐2 gene, 1 SNP in the C3 gene and 1 SNP in the mitochondrial ND2 gene. The study optometrist provided risk scores and counseling for personal protective behaviors. 101 (85%) participated; 78 (77.2%) were female. The smoking status was: 67 (66.3%) never smoked, 31 (30.7%) former smokers, and 3 (3.0%) current smokers. More than half (n=48) of participants said they were motivated to participate because they had a family member with AMD or another eye or genetic disorder. Despite low risk levels, many participants made changes as a result of the genetic testing. Twenty‐seven people reported making specific changes, including wearing sunglasses and brimmed hat, or taking vitamin supplements. Another 16 people said that they were already doing the recommended activity(ies). Interest in genetic testing for future risk of AMD was high in this population and led to continuation or improvement of eye health behaviors.

Is macular pigment spatial profile a clinical biomarker in children of AMD parents?

SummaryA central dip in macular pigment (MP) has shown to be more prevalent with age, in AMD patients, and in smokers. We investigated clinical and genetic biomarkers in non‐smoking children of AMD parents (n = 131) over 40 years of age without AMD pathology in relation to their MP spatial profile. MP peak and volume were obtained with ARIS (Visual Pathways, Inc, Prescott, AZ USA) while spatial profiles for both eyes were classified visually and objectively. We explored risk factors including serum carotenoids and in‐vivo skin carotenoids, and cardiovascular biomarkers including omega‐3 fatty acids EPA and DHA, methylenetetrahydrofolate reductase C677T and A1298C in this well‐nourished Caucasian study group. Objectively, a central dip appeared more prevalent in children of AMD patients (41%) when compared to a healthy population. Those with central dip showed increased mean MP peak and volume, decreased serum L, Z, EPA and DHA, and decreased skin carotenoids in comparison to no dip. Identifying biomarkers in children genetically susceptible to AMD and introducing lifestyle changes such as nutrient repletion could provide invaluable advice to those associated with increased risk of AMD.

A Scalable Bayesian Method for Integrating Functional Information in Genome-wide Association Studies

Genome-wide association studies (GWASs) have identified many complex loci. However, most loci reside in noncoding regions and have unknown biological functions. Integrative analysis that incorporates known functional information into GWASs can help elucidate the underlying biological mechanisms and prioritize important functional variants. Hence, we develop a flexible Bayesian variable selection model with efficient computational techniques for such integrative analysis. Different from previous approaches, our method models the effect-size distribution and probability of causality for variants with different annotations and jointly models genome-wide variants to account for linkage disequilibrium (LD), thus prioritizing associations based on the quantification of the annotations and allowing for multiple associated variants per locus. Our method dramatically improves both computational speed and posterior sampling convergence by taking advantage of the block-wise LD structures in human genomes. In simulations, our method accurately quantifies the functional enrichment and performs more powerfully for prioritizing the true associations than alternative methods, where the power gain is especially apparent when multiple associated variants in LD reside in the same locus. We applied our method to an in-depth GWAS of age-related macular degeneration with 33,976 individuals and 9,857,286 variants. We find the strongest enrichment for causality among non-synonymous variants (54× more likely to be causal, 1.4× larger effect sizes) and variants in transcription, repressed Polycomb, and enhancer regions, as well as identify five additional candidate loci beyond the 32 known AMD risk loci. In conclusion, our method is shown to efficiently integrate functional information in GWASs, helping identify functional associated-variants and underlying biology.

Correlations Between Macular, Skin, and Serum Carotenoids.

PurposeOcular and systemic measurement and imaging of the macular carotenoids lutein and zeaxanthin have been employed extensively as potential biomarkers of AMD risk. In this study, we systematically compare dual wavelength retinal autofluorescence imaging (AFI) of macular pigment with skin resonance Raman spectroscopy (RRS) and serum carotenoid levels in a clinic-based population.MethodsEighty-eight patients were recruited from retina and general ophthalmology practices from a tertiary referral center and excluded only if they did not have all three modalities tested, had a diagnosis of macular telangiectasia (MacTel) or Stargardt disease, or had poor AFI image quality. Skin, macular, and serum carotenoid levels were measured by RRS, AFI, and HPLC, respectively.ResultsSkin RRS measurements and serum zeaxanthin concentrations correlated most strongly with AFI macular pigment volume under the curve (MPVUC) measurements up to 9° eccentricity relative to MPVUC or rotationally averaged macular pigment optical density (MPOD) measurements at smaller eccentricities. These measurements were reproducible and not significantly affected by cataracts. We also found that these techniques could readily identify subjects taking oral carotenoid-containing supplements.ConclusionsLarger macular pigment volume AFI and skin RRS measurements are noninvasive, objective, and reliable methods to assess ocular and systemic carotenoid levels. They are an attractive alternative to psychophysical and optical methods that measure MPOD at a limited number of eccentricities. Consequently, skin RRS and MPVUC at 9° are both reasonable biomarkers of macular carotenoid status that could be readily adapted to research and clinical settings.

Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

BackgroundAge-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits.MethodsFor each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression.ResultsOf the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27–20.69%) and 16 of them were found to be significantly associated with AMD (Q-values < 0.01, p values from < 1.0 × 10–16 to 1.9 × 10–3). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values < 0.01, p values from 1.1 × 10–7 to 3.0 × 10–4), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD-associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis.ConclusionsWe demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common.

Visualization of Dietary Patterns and Their Associations With Age-Related Macular Degeneration.

PurposeWe aimed to visualize the relationship of predominant dietary patterns and their associations with AMD.MethodsA total of 8103 eyes from 4088 participants in the baseline Age-Related Eye Disease Study (AREDS) were classified into three groups: control (n = 2739), early AMD (n = 4599), and advanced AMD (n = 765). Using principle component analysis, two major dietary patterns and eight minor dietary patterns were characterized. Applying logistic regression in our analysis, we related dietary patterns to the prevalence of AMD. Qualitative comparative analysis by operating Boolean algebra and drawing Venn diagrams was used to visualize our findings.ResultsIn general, the eight minor patterns were subsets or extensions of either one of the two major dietary patterns (Oriental and Western patterns) and consisted of fewer characteristic foods than the two major dietary patterns. Unlike the two major patterns, which were more strongly associated with both early and advanced AMD, none of the eight minors were associated with early AMD and only four minor patterns, including the Steak pattern (odds ratio comparing the highest to lowest quintile of the pattern score = 1.73 [95% confidence interval: 1.24 to 2.41; Ptrend = 0.02]), the Breakfast pattern (0.60 [0.44 to 0.82]; Ptrend = 0.004]), the Caribbean pattern (0.64 [0.47 to 0.89; Ptrend = 0.009]), and the Peanut pattern (0.64 [0.46 to 0.89; Ptrend = 0.03]), were significantly associated with advanced AMD. Our data also suggested several potential beneficial (peanuts, pizza, coffee, and tea) and harmful (salad dressing) foods for AMD.ConclusionsOur data indicate that a diet of various healthy foods may be optimal for reducing AMD risk. The effects of some specific foods in the context of overall diet warrant further study.

Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator

BackgroundAge-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The polymorphism rs10490924 in the ARMS2 gene is highly associated with AMD and linked to an indel mutation (del443ins54), the latter inducing mRNA instability. At present, the function of the ARMS2 protein, the exact cellular sources in the retina and the biological consequences of the rs10490924 polymorphism are unclear.MethodsRecombinant ARMS2 was expressed in Pichia pastoris, and protein functions were studied regarding cell surface binding and complement activation in human serum using fluoresence-activated cell sorting (FACS) as well as laser scanning microscopy (LSM). Biolayer interferometry defined protein interactions. Furthermore, endogenous ARMS2 gene expression was studied in human blood derived monocytes and in human induced pluripotent stem cell-derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in human genotyped retinal sections and in purified monocytes derived from AMD patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes under oxidative stress was determined by Western blot analysis.ResultsHere, we demonstrate for the first time that ARMS2 functions as surface complement regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and initiates complement activation by recruiting the complement activator properdin. ARMS2-properdin complexes augment C3b surface opsonization for phagocytosis. We also demonstrate for the first time expression of ARMS2 in human monocytes especially under oxidative stress and in microglia cells of the human retina. The ARMS2 protein is absent in monocytes and also in microglia cells, derived from patients homozygous for the ARMS2 AMD risk variant (rs10490924).ConclusionsARMS2 is likely involved in complement-mediated clearance of cellular debris. As AMD patients present with accumulated proteins and lipids on Bruch’s membrane, ARMS2 protein deficiency due to the genetic risk variant might be involved in drusen formation.

Epidemiology of Reticular Pseudodrusen in Age-Related Macular Degeneration: The Rotterdam Study.

Reticular pseudodrusen (RPD) are considered to be a distinct feature in AMD. Population studies have studied the epidemiology of RPD using standard color fundus photographs (CFP). However, recent studies have shown that RPD are better imaged using near-infrared (NIR) imaging. We studied the epidemiology of RPD in a large population-based study using NIR and CFP. Participants aged 65+ years from the Rotterdam Study underwent ophthalmologic examination including NIR and CFP. Both images were graded for the presence of RPD and soft indistinct drusen (SID). Associations with demographic and environmental factors, 26 genetic variants, and total genetic risk score were analyzed using logistic regression analysis. Reticular pseudodrusen were detected in 137 (4.9%) of 2774 study participants; of these, 92.7% were detected with NIR imaging and 38% on CFP. Most eyes with RPD showed presence of SID, whereas other drusen types coincided less frequently. Reticular pseudodrusen were significantly associated with age (odds ratio [OR] 1.21, 95% Confidence Interval [CI] 1.17-1.24) and female sex (OR 2.10, 95% CI 1.41-3.13). Environmental factors did not show a significant association with RPD. Major AMD risk variants were significantly associated with RPD and SID; however, ARMS2, C3, and VEGFA were more associated with RPD (RPD vs. SID P < 0.05). Total genetic risk score did not differ significantly (P = 0.88). Detection of RPD was better with NIR imaging than on CFP in a population-based setting. Presence of RPD often coincided with presence of SID; however, they showed quantitative differences in genetic risk profile.

Associations of single nucleotide polymorphisms of VEGFR1 and smoking with age-related macular degeneration in Hui and Han populations from Ningxia region in China

Background Age-related macular degeneration (AMD) is a heritable, progressive degenerative disorder that triggers central visual impairment.Research demonstrated that the single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor 1 (VEGFR1) gene is associated with AMD in different population.However, the results varied among diversified ethnic origin composition and distinct regions. Objective This study was to investigate the associations between the SNPs of VEGFR1 genetic variants along with smoking exposure and the risk of AMD in Hui and Han ethnics in the Ningxia population in China. Methods A case-control study was conducted.Four hundreds and thirty-two AMD patients including 325 Han ethnic patients and 107 Hui ethnic patients were recruited from March 2011 to June 2015, and 906 ethnicity-and gender-matched age-related cataract patients were contemporaneously recruited as control group, including 698 Han ethnic patients and 208 Hui ethnic patients.Periphery blood sample of 5 ml was collected from the subjects and genomic DNA was prepared.Eight tagging SNPs loci were acquired to cover rs2281827, rs3936415, rs7337610, rs7981680, rs9554320, rs9554322, rs9582036 and rs9943922, and the genotypes of SNPs were detected by using MassARRAY™ time-of-flight mass spectrometry system.Chi-square test and multi-factor Logistic regression analysis were utilized to estimate the discrepancy of allele frequency and genotype distribution in Hui and Han AMD patients.Moreover, the correlation of AMD with smoking and age statue were further analyzed.This study protocol complied with Helsinki Declaration and was approved by Ethic Committee of Ningxia Eye Hospital.Written informed consent was obtained before any relevant medical examination. Results There were significant differences in the age between AMD group and control group in both Han and Hui ethnicity (Han: P=0.000; Hui: P=0.009). The smoking exposure was significantly different between AMD group and control group in Han ethnicity (P=0.000), and smoking was the independent risk factor of AMD disease in Han ethnicity of Ningxia region (odds ratio[OR]=2.622, 95% confidence interval [CI]: 1.899-3.619). The allele frequencies of SNPs were not significantly different in the AMD patients between Han and Hui ethnicity (all at P>0.05). However, the allele frequencies and genotype distribution of rs7337610 and rs9554322 SNPs were significantly different between the AMD group and control group in both Han and Hui ethnicity (all at P=0.00). The genotype distribution of rs9582036 and rs9943922 SNPs was significantly different between the AMD group and control group in Han ethnicity (P=0.02, 0.00). Allelic G of rs7337610 was the protective factor of AMD disease in Han and Hui ethnicity (OR=0.354, 95%CI: 0.288-0.435; OR=0.446, 95%CI: 0.315-0.632), while allelic C of rs9554322 was the risk factor of AMD disease in Han and Hui ethnicity (OR=1.671, 95%CI: 1.234-2.262; OR=3.661, 95%CI: 2.156-6.218). Allelic A of rs9582036 was the risk factor of AMD disease in Han ethnicity (OR=1.477, 95%CI: 1.124-1.940). Conclusions Smoking is the independent risk component for Han population with AMD.Of the eight SNPs tagged, the genotypes and alleles of rs9554322 and rs7337610 seems to confer susceptibility to AMD in both Han and Hui ethnicity, the genotypes and alleles of rs9582036 and rs9943922 confer susceptibility to AMD in only Han ethnicity. Key words: Vascular endothelial growth factor receptor-1/genetics; Macular degeneration/ethnology; Polymorphism, single nucleotide/genetics; Risk factors; Odds ratio; Genetic predisposition to disease; Alleles; Smoking/adverse effect; Case-control studies

Genetic Association Analysis of Drusen Progression.

PurposeAge-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of AMD pathogenesis.MethodsExome chip data was made available through the International AMD Genomics Consortium (IAMDGC). Drusen quantification was carried out with color fundus photographs using an automated drusen detection and quantification algorithm. A genetic risk score (GRS) was calculated per subject by summing risk allele counts at 19 common genetic risk variants weighted by their respective effect sizes. Pathway analysis of drusen progression was carried out with the software package Pathway Analysis by Randomization Incorporating Structure.ResultsWe observed significant correlation with drusen baseline area and the GRS in the age-related eye disease study (AREDS) dataset (ρ = 0.175, P = 0.006). Measures of association were not statistically significant between drusen progression and the GRS (P = 0.54). Pathway analysis revealed the cell adhesion molecules pathway as the most highly significant pathway associated with drusen progression (corrected P = 0.02).ConclusionsIn this study, we explored the potential influence of known common AMD genetic risk factors on drusen progression. Our results from the GRS analysis showed association of increasing genetic burden (from 19 AMD associated loci) to baseline drusen load but not drusen progression in the AREDS dataset while pathway analysis suggests additional genetic contributors to AMD risk.

The Association Between Serum Vitamin D Levels and Age-Related Macular Degeneration: A Systematic Meta-Analytic Review.

We conducted a meta-analysis of individual studies reporting an association between serum vitamin D levels and AMD. Relevant studies evaluating the association between serum vitamin D levels and AMD risk were identified by systematically searching four electronic literature databases (Ovid Medline, PubMed, EMBASE, and ISI Web of Science) censored by June 2015. Due to the heterogeneity of studies in categorizing serum vitamin D levels, all individual odds ratios (ORs) were recalculated and transferred for an increase of serum vitamin D levels by 10 ng/ml. Summary ORs and 95% confidence intervals (CIs) of AMD risk per 10-unit increase of serum vitamin D were obtained using standard meta-analysis. Publication bias was evaluated using funnel plots and Kendall's rank correlation tests. Ten individual studies were included and pooled in this meta-analysis. Meta-analysis of studies on AMD risk led to a pooled OR (95% CI) of 0.91 (0.69-1.22) for an increase of 25-hydroxy vitamin D by 10 ng/mL (P = 0.12). No indication for publication bias was found, but substantial heterogeneity was obtained (I2 = 79.7%, P < 0.01). Estimates from subgroup analyses also did not show statistically significant associations of serum vitamin D levels with different stages (early AMD, late AMD, and advanced AMD) and subtypes of AMD (neovascular AMD and nonneovascular AMD; P > 0.05). There is no evidence to indicate an inverse association between serum vitamin D levels and any stages and subtypes of AMD risk, but opposite results from the United States and Korea resulted in this nonsignificance. Potential difference across various study designs might exist, based on few studies reporting in heterogeneous manners so far. More studies are needed to further confirm the causality of vitamin D and AMD, especially longitudinal studies.

The effect of nutritional supplementation on the multifocal electroretinogram in healthy eyes.

Previous studies have demonstrated an increase in macular pigment optical density (MPOD) with lutein (L)-based supplementation in healthy eyes. However, not all studies have assessed whether this increase in MPOD is associated with changes to other measures of retinal function such as the multifocal ERG (mfERG). Some studies also fail to report dietary levels of L and zeaxanthin (Z). Because of the associations between increased levels of L and Z, and reduced risk of AMD, this study was designed to assess the effects of L-based supplementation on mfERG amplitudes and latencies in healthy eyes. Multifocal ERG amplitudes, visual acuity, contrast sensitivity, MPOD and dietary levels of L and Z were assessed in this longitudinal, randomized clinical trial. Fifty-two healthy eyes from 52 participants were randomly allocated to receive a L-based supplement (treated group), or no supplement (non-treated group). There were 25 subjects aged 18-77 (mean age ± SD; 48 ± 17) in the treated group and 27 subjects aged 21-69 (mean age ± SD; 43 ± 16) in the non-treated group. All participants attended for three visits: visit one at baseline, visit two at 20 weeks and visit three at 40 weeks. A statistically significant increase in MPOD (F = 17.0, p ≤ 0.001) and shortening of mfERG ring 2 P1 latency (F = 3.69, p = 0.04) was seen in the treated group. Although the results were not clinically significant, the reported trend for improvement in MPOD and mfERG outcomes warrants further investigation.

Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration: A Meta-Analysis.

ImportanceThe fellow eye of patients with unilateral neovascular age-related degeneration (nAMD) is at increased risk of developing late AMD. Several cohort studies have evaluated the prevalence of pseudodrusen and the association between pseudodrusen and late AMD in the fellow eye of patients with unilateral nAMD. However, these studies have limited sample sizes and their results are inconsistent.ObjectiveTo evaluate the prevalence rate of pseudodrusen, and the association between pseudodrusen and incidence of late AMD (nAMD and geographic atrophy (GA)) in the fellow eye of patients with unilateral nAMD.Data SourcesThe PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched up to July 2015, as well as other systematic reviews.Study SelectionAll cohort studies for pseudodrusen with late AMD in the fellow eye of patients with unilateral nAMD.Data Extraction and SynthesisThe numbers of patients with and without pseudodrusen at baseline and the numbers of incident nAMD and GA during follow up among patients with and without pseudodrusen were independently extracted by 2 authors. The results were pooled using random-effects meta-analysis. Heterogeneity was assessed using the I2 test.Main Outcome MeasuresPrevalence rate of pseudodrusen, risk ratios (RRs) and their 95% confidence intervals (95% CIs) for associations between pseudodrusen and the incidence of nAMD and GA in the fellow eye.ResultsFive cohort studies (N = 677 patients) from 8 countries across 4 continents were included. The pooled prevalence rate of pseudodrusen in the fellow eye was 48.1% (95% Cl: 36.7–59.5%, I2 = 87%). Pseudodrusen were associated with an increased risk of nAMD (RR = 1.54, 95% Cl: 1.10–2.16, I2 = 42%), GA (RR = 4.70, 95% Cl: 1.22–18.1, I2 = 64%), and late AMD (RR = 2.03, 95% Cl: 1.35–3.06, I2 = 60%).ConclusionsFor patients with unilateral nAMD, pseudodrusen were present in about half of the fellow eyes. The presence of pseudodrusen was associated with a 1.5 times higher risk of developing nAMD, a 4.7 times higher risk of developing GA, and a 2 times higher risk of developing late AMD. Pseudodrusen should be considered in evaluating the risk of late AMD development; however, due to considerable heterogeneity across these studies, a larger study is needed to validate these findings.

Effect of residual monomer from polyacrylamide on head lettuce grown in peat substrate

The paper investigates the migration of the acrylamide monomer (AMD) to lettuce chosen as a test plant growing in an organic medium (peat substrate). Polyacrylamide (PAM)-based flocculant added to the growing medium contained no more than 1000 mg kg−1 of AMD. Plants were grown with varied doses of PAM preparation (0.5–3.0 mg dm–3 of peat substrate) to compare the results with the control sample. The determination of AMD content, chlorophyll content, weight of the lettuce head, and also analysis of macro- and micro-elements in lyophilised test material was made under the same analytical conditions. The results showed that lettuce plants absorb AMD to the leaves from the peat substrate. The AMD uptake has a negative impact on the growth of lettuce. It reduces the average fresh weight of heads and destabilises the mineral composition of the plant. Therefore, concern related to the transfer risk of the residual AMD from sludge used for organic fertilisation of edible plants still remains a crucial question from a food and consumer safety point of view. To ensure consumer safety, the fate of the AMD following the application of PAM to cropland should be carefully monitored in the whole food chain.

Associations of the G1961E and D2177N variants in ABCA4 and the risk of age-related macular degeneration

ObjectiveThe aim of this study was to identify the relationship between G1961E and D2177N variants in the ABCA4 gene with AMD susceptibility. Design and methodsAll eligible studies published up to October 2014 were obtained from MEDLINE, EMBASE, and ISI Web of Science. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was calculated to evaluate the strength of this association. ResultsTwenty-four studies enrolling 4580 AMD cases and 5180 controls were identified. Both G1961E (OR=3.22, 95% CI: 1.74–5.95) and D2177N (OR=2.36, 95% CI: 1.41–3.93) variations showed significant associations with increased risk of AMD. In addition, a more significant relationship in the D2177N mutation with increased risk for AMD was found in Americans (OR=4.31, 95% CI: 1.90–9.73), while no association was demonstrated in Europeans. For Asians, no carriers of the risk factor A allele in either variant were detected in any of AMD patients and control subjects. ConclusionsSignificant evidence was found for a relationship between the G1961E and D2177N variants in ABCA4 with increased susceptibility to AMD, specifically for Americans. However, large-scale studies are still required to further validate these findings in different ethnicities.

American Minor Dietary Patterns and Age‐related Macular Degeneration

Objective:To evaluate the relationships between American minor dietary patterns and AMD.Methods:8,103 eyes from 4,088 eligible participants in the baseline Age‐Related Eye Disease Study (AREDS) were classified into control (n=2,739), early AMD (n=4,599), and advanced AMD (n=765) according to the AREDS AMD Classification System. Using food consumption data collected by a 90‐item food frequency questionnaire, eight minor dietary patterns were characterized by principle component analysis based on 37 food groups.Results:The eight minor dietary patterns were named Steak, Breakfast, Salad, Caribbean, Pizza, Peanut, Alcohol, and Beverage patterns. For advanced AMD, the multivariate‐adjusted OR comparing the highest to lowest quintile of the pattern score was 1.73 (95% CI: 1.24 to 2.41; Ptrend=0.02) for the Steak pattern, 0.60 (95% CI: 0.44 to 0.82; Ptrend=0.004) for the Breakfast pattern, 0.64 (95% CI: 0.47 to 0.89; Ptrend=0.009) for the Caribbean pattern, and 0.64 (95% CI: 0.46 to 0.89; Ptrend=0.03) for the Peanut pattern.ConclusionsThis cross‐sectional analysis indicates that a diet characterized by higher intake of leafy and salad vegetables alone, such as the Salad pattern, may be insufficient to provide a protection against AMD, and some foods that have not been recognized previously, such as peanuts, may be protective against AMD. These results, in conjunction with our previous analysis of major American dietary patterns, suggest that a diet consisted of diverse healthy foods may be the best dietary option for reducing AMD risk.

Polymorphisms of complement genes and ARMS2/HTRA1 in patients with age-related macular degeneration in Ningxia,China

Background Age-related macular degeneration (AMD) is the main cause of irreversible loss of central vision in old population.The incidence of AMD is increasing year by year,but the mechanism is not clearly understood. Objective This study was to investigate the association between genetic variants and the risk of AMD in Ningxia population. Methods This study was approved by Ethic Committee of Ningxia People's Hospital and complied with the Helsinki Declaration.Written informed consent was obtained from each subject.One hundred and fifty patients with AMD and 145 ethnicity- and gender-matched controls were recruited in Ningxia Eye Hospital from January 2012 to March 2013.All individuals underwent comprehensive eye examinations and genomic DNA was prepared from peripheral blood.The single nucleotide polymorphisms (SNPs) of 8 susceptibility loci in four candidate genes,including complement factor H (CFH),complement factor B (CFB),age-related maculopathy susceptibility 2 (ARMS2) and high temperature required factor A1 (HTRA1),were genotyped with Mass Array and MALDI-TOF technique by Sequenom platform.The distribution of genotype was tested for Hardy-Weinberge equilibrium (HWE).The differences of genotype distribution of allele and haplotype frequencies were compared between patients and controls using chi-squared test and the P value was significant at <0.006 level after correction of age,and the relationship of genotype distribution with AMD was evaluated by Logistic regression analysis.Measures of linkage disequilibrium (LD) was carried out by Haploview. Results All the genetypes met HWE.Seven SNPs were found to be different in the genotypic distributions and allele frequencies between patients and normal controls (all at P<0.05),however,after Bonferroni correction,the differences of only four SNPs were significant between the patients and controls in the genotype and allele distributions,including the SNPs of rs10737680 and rs1410996 in CFH gene,the SNP of rs10490924 in ARMS2 gene and SNP of rs11200638 in HTRA1 gene. The allele distributions of rs800292 (Pallele=0.006,OR=1.643,95%CI:1.155-2.336) in CFH and rs641153 (Pallele=0.002,OR=0.273,95%CI:0.120-0.620) in CFB were significantly associated with AMD.In addition,five SNPs in CFH gene were consisted of two blocks after analysis by Haploview.In addition,five SNPs in CFH were consisted of two blocks after analysis by Haploview.The first one SNPs (including rs551397 and rs800292) and another one SNPs (including rs12124794,rs10737680) and rs1410996 were in strong linkage disequilibrium (D'=1.00).After 50 000 permutations,the GC and AT haplotypes of the first block and the AAC,TCT and ACT haplotypes in the second block were significantly different between AMD patients and controls (P=0.010,0.010,0.001,0.041 and 0.033,respectively).The allel T of rs641153 was a protective factor of AMD (P=0.002,OR=0.273,95%CI:0.120-0.620). Conclusions The SNPs rs10737680 and rs1410996 in CFH, rs10490924 of ARMS2 gene and rs11200638 of HTRA1 gene are associated with AMD in Ningxia population. Key words: Aged; Complement factor/genetics; Gene frequency; Macular degeneration/genetics; Polymorphisms, genetic; Genetic predisposition to diseases

New loci and coding variants confer risk for age-related macular degeneration in East Asians.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10−22). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l−1 (P=5.82 × 10−21) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10−18), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10−11) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10−8). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

Joint Effect of CFH and ARMS2/HTRA1 Polymorphisms on Neovascular Age-Related Macular Degeneration in Chinese Population.

Purpose. The etiology of neovascular age-related macular degeneration (nAMD) cannot be completely explained by identified environmental risk factors or single-locus gene variants. This study was to explore the potential interactions among gene variants on nAMD in Chinese population. Methods. 43 SNPs located in different genes were genotyped in 932 Chinese individuals (464 nAMD patients and 468 controls). We explored the potential interactions among gene variants using generalized multifactor dimensionality reduction (GMDR) algorithm and the method to measure the departure from the additivity model. Results. The joint effect that involved CFH rs1061170 and HTRA1 rs3793917 was shown statistically significant (P < 0.001) with the highest cross-validation consistency (10/10) and the best testing balanced accuracy (64.50%). In addition, based on the method to measure the departure from the additivity model, the synergy index (S) was 2.63 (1.09–6.38) and the attributable proportion due to interaction (AP) was 55.7% (21.4%–89.9%), which suggested that a common pathway may exist for these genes for nAMD. Those who carried CC for rs3793917 and TC/CC for rs1061170 were at the highest risk of nAMD (OR: 9.76, 95% CI: 4.65–20.51). Conclusions. Evidence that the joint effect that involved CFH and ARMS2/HTRA1 may contribute to the risk of neovascular AMD in Chinese population was obtained.

Detection and biological activities of carboxyethylpyrrole ethanolamine phospholipids (CEP-EPs).

Oxidation of docosahexaenoate phospholipids produces 4-hydroxy-7-oxo-hept-5-eonyl phospholipids (HOHA-PLs) that react with protein lysyl ε-amino residues to generate 2-ω-carboxyethylpyrrole (CEP) derivatives, endogenous factors that induce angiogenesis in the retina and tumors. It seemed likely, but remained unproven, that HOHA-PLs react with ethanolamine phospholipids (EPs) in vivo to generate CEP-EPs. We now show that CEP-EPs are present in human blood at 4.6-fold higher levels in age-related macular degeneration plasma than in normal plasma. We also show that CEP-EPs are pro-angiogenic, inducing tube formation by human umbilical vein endothelial cells by activating Toll-like receptor 2. CEP-EP levels may be a useful biomarker for clinical assessment of AMD risk and CEP-associated tumor progression and a tool for monitoring the efficacy of therapeutic interventions.