Prediction of severe retinopathy of prematurity using the weight gain, insulin-like growth factor 1, and neonatal retinopathy of prematurity algorithm in a Japanese population of preterm infants.

PURPOSE: To retrospectively investigate the sensitivity and specificity of weight gain, insulin-like growth factor 1, and neonatal retinopathy of prematurity (WINROP) algorithm for the prediction of severe retinopathy of prematurity (ROP) in a Japanese population of preterm infants. The WINROP algorithm is a tool based on postnatal weight gain. STUDY DESIGN: Retrospective cohort study. METHODS: The medical records of preterm infants born between January 2011 and March 2017 were retrospectively reviewed. Infants born after 33 weeks of gestation were excluded based on the indications of the WINROP algorithm. Postnatal weight was recorded weekly on the WINROP system until postmenstrual week 36. The sensitivity and specificity of the WINROP algorithm were analyzed. RESULTS: In total, 278 infants were included in this study. Based on the WINROP algorithm 110 of these infants were predicted to be at low risk for developing severe ROP and 105 did not develop severe ROP. Based on the WINROP algorithm 168 infants were predicted to be at high risk for developing severe ROP　and 27 developed severe ROP. Thus, the sensitivity of the WINROP algorithm was 84.4% and the specificity 42.7%. CONCLUSION: The WINROP algorithm could be used for preterm infants (gestational age of <28 weeks) without a complicated hospital course. Modification of the algorithm will improve its sensitivity and specificity for the Japanese population.

The association of elastin gene variants with two angiographic subtypes of polypoidal choroidal vasculopathy.

OBJECTIVE: To compare the association of elastin (ELN) gene variants between two different angiographic phenotypes of polypoidal choroidal vasculopathy (PCV). METHODS: We included 411 treatment-naïve PCV patients and 350 controls in the present study. PCV was classified into two phenotypes (152 Type 1 and 259 Type 2) according to the presence or absence of feeding vessels found in indocyanine-green angiography. Single nucleotide polymorphisms (SNPs) in the ELN region including rs868005, rs884843, rs2301995, rs13239907 and rs2856728 were genotyped using TaqMan Genotyping Assays. RESULTS: In the allelic association analyses, rs868005 showed the strongest association with Type 2 PCV (allelic odds ratio 1.56; p = 7.4x10(-6)), while no SNP was significantly associated with Type 1 PCV. Genotype association analyses revealed the significant association of rs868005 with Type 2 PCV in log additive model and predominant model (odds ratio 1.75; p = 1.5x10(-6) and odds ratio 1.60; p = 0.0044, respectively), but not with Type 1 PCV. These findings were further corroborated by another control group in the literature. CONCLUSIONS: There may be significantly different associations in genetic variants of elastin between two angiographic phenotypes of PCV.

Comparison of the outcomes of photodynamic therapy between two angiographic subtypes of polypoidal choroidal vasculopathy.

BACKGROUND: To compare the outcomes of photodynamic therapy (PDT) between two different angiographic subtypes of polypoidal choroidal vasculopathy (PCV). METHODS: Ninety-three consecutive cases of PCV were classified into two phenotypes (42 type 1 and 51 type 2) according to the presence or absence of feeding vessels found on indocyanine green angiography. Full-dose PDT and retreatments were performed every 3 months as needed based on the findings on angiography. The best-corrected visual acuity (BCVA) was compared as the main outcome between type 1 and type 2 PCV up to 12 months after the initial PDT. RESULTS: The baseline greatest linear dimension (GLD) was significantly larger in type 1 PCV than type 2 PCV. The mean BCVA was significantly improved from baseline in type 2 PCV, while no improvement was found in type 1 PCV. Analysis with matching the GLD between both PCV subtypes did not change the original results. CONCLUSIONS: There may be a significantly different response to PDT between two angiographic phenotypes of PCV.

Evaluation of clinical and genetic indicators for the early response to intravitreal ranibizumab in exudative age-related macular degeneration.

AIM: This study was conducted to evaluate the possible clinical and genetic indicators for an early response to intravitreal ranibizumab (IVR) in exudative age-related macular degeneration (AMD). PATIENTS & METHODS: The records of 120 eyes from 120 Japanese patients with treatment-naive exudative AMD were retrospectively reviewed. Three consecutive IVR treatments were performed every month. Achievement of anatomical resolution was evaluated by ophthalmoscopy and optical coherence tomography. Multivariable logistic regression analysis was conducted by analyzing SNPs in the ARMS2 locus (A69S) and in the CFH gene (I62V and Y402H), in addition to clinical factors. RESULTS: The mean central retinal thickness of overall patients was significantly decreased (-120.1 ± 122.8 µm, p = 2.7 × 10(-19)) at 3 months after the initial treatment. In the logistic regression analysis, the poor anatomical resolution of the lesion at 3 months was associated with the combination of CFH I62V + CFH Y402H variants (p = 0.0021), and the polypoidal choroidal vasculopathy lesions (p = 0.044). CONCLUSION: The CFH variants and the polypoidal choroidal vasculopathy lesion may influence the early anatomical resolution with IVR in exudative AMD.

Common variants in the complement factor H gene confer genetic susceptibility to central serous chorioretinopathy.

PURPOSE: To investigate whether complement factor H (CFH) gene DNA variants are associated with central serous chorioretinopathy (CSCR). DESIGN: Cross-sectional study. PARTICIPANTS: A case-control group of 140 CSCR subjects and 2 different control groups: 934 population-based controls and 335 hospital-based controls. METHODS: Five single-nucleotide polymorphisms (SNPs) in CFH (rs3753394, rs800292, rs2284664, rs1329428, and rs106548) were evaluated for association with CSCR in 2 separate association analyses comparing CSCR subjects with 2 different control groups. Genotyping was performed using TaqMan technology (Applied Biosystems, Foster City, CA). MAIN OUTCOME MEASURES: Allele and haplotype frequencies of the 5 variants in the CFH region. RESULTS: Highly statistically significant associations with CSCR were found for the 5 SNPs. The strongest association was observed with rs1329428 (allelic P = 6.44×10(-6); odds ratio, 1.79; 95% confidence interval [CI], 1.39-2.31, cases vs. population-based controls), which accounted for 35.5% of the population-attributable fraction for CSCR. Consistent with the analysis, rs1329428 showed the strongest disease association (allelic P = 1.00×10(-5); odds ratio, 1.89; 95% CI, 1.42-2.50) in comparing cases with hospital-based controls. The second most strongly associated SNP, rs1065489, was correlated highly with the most strongly associated SNP, rs1329428 (r(2) = 0.77), and their effects could not be distinguished statistically from each other. A conditional logistic regression analysis revealed that the 2 highly correlated SNPs, rs1329428 and rs1065489, account for the association signals detected at the CFH locus. CONCLUSIONS: We identified a novel association between CSCR and common CFH polymorphisms. Our findings support the involvement of CFH in the pathogenesis of CSCR; exploration of the role of CFH could yield important insights into the biological mechanisms underlying CSCR. Our identification of common CFH variants as susceptibility elements for CSCR will open new avenues for research, leading to a better understanding of CSCR pathogenesis and ultimately to the development of improved therapeutic approaches.

A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population.

BACKGROUND: Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32 × 10(-4); odds ratio = 0.48 [95% CI = 0.31-0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway. CONCLUSIONS: Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations.

Difference between age-related macular degeneration and polypoidal choroidal vasculopathy in the hereditary contribution of the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2).

PURPOSE: To investigate whether the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2) has a different hereditary contribution in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: We initially conducted a comparative genetic analysis of neovascular AMD and PCV, genotyping the ARMS2 A69S variant in 181 subjects with neovascular AMD, 198 subjects with PCV, and 203 controls in a Japanese population. Genotyping was conducted using TaqMan technology. Results were then integrated into a meta-analysis of previous studies representing an assessment of the association between the ARMS2 A69S variant and neovascular AMD and/or PCV, comprising a total of 3,828 subjects of Asian descent. The Q-statistic test was used to assess between-study heterogeneity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a fixed effects model. RESULTS: The genetic effect of the A69S variant was stronger in neovascular AMD (allelic summary OR=3.09 [95% CI, 2.71-3.51], fixed effects p<0.001) than in PCV (allelic summary OR=2.13 [95% CI, 1.91-2.38], fixed effects p<0.001). The pooled risk allele frequency was significantly higher in neovascular AMD (64.7%) than in PCV (55.6%). The population attributable risks for the variant allele were estimated to be 43.9% (95% CI, 39.0%-48.4%) and 29.7% (95% CI, 25.4%-34.0%) for neovascular AMD and PCV, respectively. No significant between-study heterogeneity was observed in any statistical analysis in this meta-analysis. CONCLUSIONS: Our meta-analysis provides substantial evidence that the ARMS2 A69S variant confers a significantly higher risk of neovascular AMD than PCV. Furthermore, there is compelling evidence that the risk attributable to the A69S variant differs between geographic atrophy and neovascular AMD. Together with defining the molecular basis of susceptibility, understanding the relationships between this genomic region and disease subtypes will yield important insights, elucidating the biologic architecture of this phenotypically heterogeneous disorder.