Near-infrared reflectance imaging of neovascular age-related macular degeneration

Contains fulltext : 81007.pdf (publisher's version ) (Closed access)PURPOSE: To evaluate various types of neovascular age-related macular degeneration (AMD) by near-infrared fundus reflectance (NIR) as compared to fundus fluorescein angiography (FFA) and to test NIR for assessment of leakage due to choroidal neovascularization (CNV). PATIENTS AND METHODS: Thirty-three patients with neovascular AMD (cases) and 20 age-matched patients with non-exudative AMD and healthy subjects (controls) were examined with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2). NIR images of neovascular AMD were qualitatively compared to the corresponding FFA and to age-matched controls. CNV membranes and exudation areas were manually segmented on FFA and NIR and analyzed quantitatively. Results : Of all cases included, five eyes had classic CNV, six had minimal classic lesions, 15 occult CNV's and seven eyes had retinal angiomatous proliferation (RAP). A dark halo on NIR was found in all cases and showed high correspondence to leakage on FFA (r (2) = 0.93; p < 0,0005). In classic CNV and minimal classic CNV, the classic part of the lesion on FFA revealed strong correlation to a dark core surrounded by a bright reflecting ring on NIR (r (2) = 0.88; p < 0.0005). Occult parts on FFA of minimal classic CNV and occult CNV lesions appeared as poorly demarcated, jagged areas of increased NIR. RAP was characterized by speckled NIR located at the intraretinal neovascular complex. CONCLUSIONS: NIR imaging in neovascular AMD revealed characteristic alterations depending on the type of CNV. These changes may reflect histological differences of the lesions. Leakage caused local darkening of NIR, presumably originating from increased light-scattering and absorbance by fluid accumulation and sub-cellular structure alterations

A comparison of genomic profiles of complex diseases under different models

Background: Various approaches are being used to predict individual risk to polygenic diseases from data provided by genome-wide association studies. As there are substantial differences between the diseases investigated, the data sets used and the way they are tested, it is difficult to assess which models are more suitable for this task. Results: We compared different approaches for seven complex diseases provided by the Wellcome Trust Case Control Consortium (WTCCC) under a within-study validation approach. Risk models were inferred using a variety of learning machines and assumptions about the underlying genetic model, including a haplotype-based approach with different haplotype lengths and different thresholds in association levels to choose loci as part of the predictive model. In accordance with previous work, our results generally showed low accuracy considering disease heritability and population prevalence. However, the boosting algorithm returned a predictive area under the ROC curve (AUC) of 0.8805 for Type 1 diabetes (T1D) and 0.8087 for rheumatoid arthritis, both clearly over the AUC obtained by other approaches and over 0.75, which is the minimum required for a disease to be successfully tested on a sample at risk, which means that boosting is a promising approach. Its good performance seems to be related to its robustness to redundant data, as in the case of genome-wide data sets due to linkage disequilibrium. Conclusions: In view of our results, the boosting approach may be suitable for modeling individual predisposition to Type 1 diabetes and rheumatoid arthritis based on genome-wide data and should be considered for more in-depth research.This work was supported by the Spanish Secretary of Research, Development and Innovation [TIN2010-20900-C04-1]; the Spanish Health Institute Carlos III [PI13/02714]and [PI13/01527] and the Andalusian Research Program under project P08-TIC-03717 with the help of the European Regional Development Fund (ERDF). The authors are very grateful to the reviewers, as they believe that their comments have helped to substantially improve the quality of the paper

Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in Western countries. Numerous risk factors have been reported but the evidence and strength of association is variable. We aimed to identify those risk factors with strong levels of evidence which could be easily assessed by physicians or ophthalmologists to implement preventive interventions or address current behaviours. METHODS: A systematic review identified 18 prospective and cross-sectional studies and 6 case control studies involving 113,780 persons with 17,236 cases of late AMD that included an estimate of the association between late AMD and at least one of 16 pre-selected risk factors. Fixed-effects meta-analyses were conducted for each factor to combine odds ratio (OR) and/or relative risk (RR) outcomes across studies by study design. Overall raw point estimates of each risk factor and associated 95% confidence intervals (CI) were calculated. RESULTS: Increasing age, current cigarette smoking, previous cataract surgery, and a family history of AMD showed strong and consistent associations with late AMD. Risk factors with moderate and consistent associations were higher body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen. Risk factors with weaker and inconsistent associations were gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease, and serum total and HDL cholesterol and triglyceride levels. CONCLUSIONS: Smoking, previous cataract surgery and a family history of AMD are consistent risk factors for AMD. Cardiovascular risk factors are also associated with AMD. Knowledge of these risk factors that may be easily assessed by physicians and general ophthalmologists may assist in identification and appropriate referral of persons at risk of AMD

Modelling the Genetic Risk in Age-Related Macular Degeneration

Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69–2.05) than patients aged 75 and above (1.45, 95% CI: 1.36–1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11–1131.96) for individuals in the highest category (GRS 3.44–5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS −0.05–1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

BACKGROUND: Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. METHODOLOGY/PRINCIPAL FINDINGS: A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. CONCLUSIONS/SIGNIFICANCE: The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy

Evaluation of genetic susceptibility to childhood allergy and asthma in an African American urban population

<p>Abstract</p> <p>Background</p> <p>Asthma and allergy represent complex phenotypes, which disproportionately burden ethnic minorities in the United States. Strong evidence for genomic factors predisposing subjects to asthma/allergy is available. However, methods to utilize this information to identify high risk groups are variable and replication of genetic associations in African Americans is warranted.</p> <p>Methods</p> <p>We evaluated 41 single nucleotide polymorphisms (SNP) and a deletion corresponding to 11 genes demonstrating association with asthma in the literature, for association with asthma, atopy, testing positive for food allergens, eosinophilia, and total serum IgE among 141 African American children living in Detroit, Michigan. Independent SNP and haplotype associations were investigated for association with each trait, and subsequently assessed in concert using a genetic risk score (GRS).</p> <p>Results</p> <p>Statistically significant associations with asthma were observed for SNPs in <it>GSTM1, MS4A2</it>, and <it>GSTP1 </it>genes, after correction for multiple testing. Chromosome 11 haplotype CTACGAGGCC (corresponding to <it>MS4A2 </it>rs574700, rs1441586, rs556917, rs502581, rs502419 and <it>GSTP1 </it>rs6591256, rs17593068, rs1695, rs1871042, rs947895) was associated with a nearly five-fold increase in the odds of asthma (Odds Ratio (OR) = 4.8, <it>p </it>= 0.007). The GRS was significantly associated with a higher odds of asthma (OR = 1.61, 95% Confidence Interval = 1.21, 2.13; <it>p </it>= 0.001).</p> <p>Conclusions</p> <p>Variation in genes associated with asthma in predominantly non-African ethnic groups contributed to increased odds of asthma in this African American study population. Evaluating all significant variants in concert helped to identify the highest risk subset of this group.</p

Inflammation gene variants and susceptibility to albuminuria in the U.S. population: analysis in the Third National Health and Nutrition Examination Survey (NHANES III), 1991-1994

<p>Abstract</p> <p>Background</p> <p>Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. While the underlying etiology is unclear, chronic, low-grade inflammation is a suspected key factor. Genetic variants within genes involved in inflammatory processes may, therefore, contribute to the development of albuminuria.</p> <p>Methods</p> <p>We evaluated 60 polymorphisms within 27 inflammatory response genes in participants from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States. Albuminuria was evaluated as logarithm-transformed albumin-to-creatinine ratio (ACR), as ACR ≥ 30 mg/g, and as ACR above sex-specific thresholds. Multivariable linear regression and haplotype trend analyses were conducted to test for genetic associations in 5321 participants aged 20 years or older. Differences in allele and genotype distributions among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans were tested in additive and codominant genetic models.</p> <p>Results</p> <p>Variants in several genes were found to be marginally associated (uncorrected P value < 0.05) with log(ACR) in at least one race/ethnic group, but none remained significant in crude or fully-adjusted models when correcting for the false-discovery rate (FDR). In analyses of sex-specific albuminuria, <it>IL1B </it>(rs1143623) among Mexican Americans remained significantly associated with increased odds, while <it>IL1B </it>(rs1143623), <it>CRP </it>(rs1800947) and <it>NOS3 </it>(rs2070744) were significantly associated with ACR ≥ 30 mg/g in this population (additive models, FDR-P < 0.05). In contrast, no variants were found to be associated with albuminuria among non-Hispanic blacks after adjustment for multiple testing. The only variant among non-Hispanic whites significantly associated with any outcome was <it>TNF </it>rs1800750, which failed the test for Hardy-Weinberg proportions in this population. Haplotypes within <it>MBL2</it>, <it>CRP</it>, <it>ADRB2, IL4R</it>, <it>NOS3</it>, and <it>VDR </it>were significantly associated (FDR-P < 0.05) with log(ACR) or albuminuria in at least one race/ethnic group.</p> <p>Conclusions</p> <p>Our findings suggest a small role for genetic variation within inflammation-related genes to the susceptibility to albuminuria. Additional studies are needed to further assess whether genetic variation in these, and untested, inflammation genes alter the susceptibility to kidney damage.</p