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1.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
2.  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.
PMCID: PMC3217135  PMID: 21882290
age-related macular degeneration; AMD; apolipoprotein E; APOE; case-control association study
3.  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.
PMCID: PMC3145394  PMID: 21498624
aged; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; apolipoproteins E; longevity; meta-analysis; multicenter study
4.  DHA supplementation for late onset Stargardt disease: NAT-3 study 
We analyzed the effects of a docosahexaenoic acid (DHA) supplementation in patients affected with late onset Stargardt disease (STGD).
DHA (840 mg/day) was given to 20 STGD patients for six months. A complete ophthalmologic examination, including best-corrected visual acuity (BCVA) and multifocal electroretinogram (mfERG), was performed at inclusion day 0 (D0) and at month 6 (M6).
Overall, no statistical differences have been observed at M6 vs D0 as regards BCVA and mfERG (P > 0.05). Mild Improvement of BCVA and improvement of mfERG was noted in seven/40 eyes of four/20 patients. In the first patient, the peak of the a wave increased from 66 nV/deg2 to 75.4 nV/deg2 in the right eye (RE) and 24.5 nV/deg2 to 49.1 nV/deg2 in the left eye (LE). The peak of the b wave improved from 122 nV/deg2 to 157 nV/deg2 in the RE, and 102 nV/deg2 to 149 nV/deg2 in the LE. In the second patient peaks of the a and b waves respectively increased from 11.8 nV/deg2 to 72.1 nV/deg2 and 53 nV/deg2 to 185 nV/deg2 in the RE. In the third patient the peak of the a wave increased from 37 nV/deg2 to 43 nV/deg2 in the RE, and from 31 nV/deg2 to 45 nV/deg2 in the LE; the peak of the b wave improved from 70 nV/deg2 to 89 nV/deg2 in the RE, and from 101 nV/deg2 to 108 nV/deg2 in the LE. In the fourth patient, the peak of the a wave increased from 39 nV/deg2 to 42 nV/deg2 in the RE, and from 40 nV/deg2 to 43 nV/deg2 in the LE; the peak of the b wave improved from 86 nV/deg2 to 94 nV/deg2 in the RE, and from 87 nV/deg2 to 107 nV/deg2 in the LE.
DHA seems to influence some functional parameters in patients affected with STGD. However, no short-term benefit should be expected from DHA supplementation.
PMCID: PMC2909886  PMID: 20668719
docosahexaenoic acid (DHA); multifocal electroretinogram; omega-3; polyunsaturated fatty acid; retinal dystrophy; Stargardt disease
5.  A new approach for visualisation of dye leakage in fluorescein angiography 
Fluorescein angiography (FA) is the more common investigation performed for macular diseases.1 Frozen FA pictures are obtained but direct visualisation of the kinetics of FA is possible only once, by the investigator. The kinetics of FA examination is imagined from static FA pictures based on our experience.23 We evaluated a new software that re‐create automatic pseudo‐movie from static pictures, in order to share the visualisation of dye leakage.
EyeToolkit software (EDC Lamy EyeToolkit software, EDC LAMY, Carvin, France) performs an automatic and rapid overlay (0.5 to 3 seconds) from the different angiographic frames. Five images from the same examination, from early to late phase, are required to generate a movie. The resulting movies could be seen either with the EyeToolkit software or be exported to video format. We submitted a minimum of six images issued from printed photographs or any digital instrument (Topcon retinal camera, TRC‐50, Topcon, Tokyo, Japan; Heidelberg Retina Angiograph, HRA 2, Heidelberg Engineering, Heidelberg, Germany), to the EyeToolkit software: sequences of fluorescein angiograms of patients harbouring various patterns of exudative age‐related macular degeneration (AMD), with or without treatment, were selected in order to visualise active leakage of dye and to differentiate it from staining. In addition, we submitted to the EyeToolkit software images issued from one single FA examination (early phase to 10′) in case of central serous chorioretinopathy (CSC), in order to see the kinetics of the leakage and to visualise leakage of dye from active areas of CSC.
We evaluated two kinds of leakage: chorio‐retinal leakage from choroidal new vessels (CNVs) due to AMD, and retinal leakage from active areas of CSC. In exudative AMD patients, the rapid overlay (<10”) applied in a movie mode obviously demonstrated the progressive enlargement of the hyperfluorescence, materialising the leakage of fluorescein from CNVs. The FA movies generated with EyeToolkit permitted to clearly see the active leakage from a newly diagnosed classic CNV (Video 1), and from a newly diagnosed minimally classic CNV (Video 2). Moreover, the FA movies generated with EyeToolkit permitted to easily detect the minimal leakage from a still active classic choroidal neovascularisation previously treated by photodynamic therapy (PDT) (Video 3), and to visualise the filling of the vascularised pigment epithelium detachment from an occult choroidal neovascularisation previously treated by PDT (Video 4). In CSC, the FA movies generated with EyeToolkit permitted to see the kinetics of the classic smokestack‐type leakage (Video 5) and to easily visualise leakage of dye from active areas of CSC (Video 6). EyeToolkit software is a new automatic and efficient tool for a rapid overlay of images, obtaining an angiographic movie from any image. It leads to easy visualisation of leakage from CNVs and from active areas of CSC; thus, owing to the easy differentiation of active leakage from staining, EyeToolkit software would seem particularly helpful for the decision of treatment and re‐treatment. Easy visibility of the kinetics of the dye in angiography, in a movie mode, also represents a useful approach for teaching. Based on this preliminary analysis, this software can be considered for (1) recreating pseudo‐kinetics of dye in retinal angiography, (2) easy sharing of retinal angiograhy; voice comments can be included within the file, and (3) teaching and e‐learning. The comparative evaluation of the generated movies versus classic angiographic pictures must validate its use for diagnosis and indications of treatment.
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PMCID: PMC2095509  PMID: 18024812

Results 1-5 (5)