Associations of cigarette smoking but not serum fatty acids with age-related macular degeneration in a Japanese population.

PURPOSE: To assess modifiable environmental risk factors and protective factors for age-related macular degeneration (AMD) in a native Japanese population. DESIGN: A case-control study. PARTICIPANTS: We included 422 case-control samples composed of 279 consecutive AMD cases and 143 controls. METHODS: Information regarding systemic conditions and lifestyle were documented in each subject by standardized questionnaire including age, gender, smoking history, body mass index (BMI), and history of cardiovascular disease, hypertension, and diabetes. Serum fatty acids profiles were analyzed by gas chromatography performed on blood samples taken from each study participant. Logistic regression and multiple comparison analyses were utilized in this study. MAIN OUTCOME MEASURES: Population-specific information assessing systemic conditions, lifestyle, and serum fatty acid profiles. RESULTS: Among environmental factors analyzed cigarette smoking showed the most significant association with development of all AMD (P<0.00001; odds ratio [OR], 4.06; 95% confidence interval [CI], 2.22-7.43), typical neovascular AMD (P<0.0001, OR, 4.59; 95% CI, 2.29-9.18), and polypoidal choroidal vasculopathy (P<0.001; OR, 4.87; 95% CI, 1.96-12.1). Hypertension and BMI showed a mild association with AMD. Although male prevalence was significantly higher in all case groups than in controls with conventional Scheffe correction, there was no association of gender with AMD development when logistic regression analysis was used to adjust for cigarette smoking. There was no difference in fatty acid profiles, except for a mild association of eicosapentaenoic acid concentration in the all AMD group. CONCLUSIONS: In the Japanese population studied, cigarette smoking influenced the risk of AMD but fractionated serum fatty acid levels did not. Although prior reports indicate a male predominance in Japanese patients with AMD, this study demonstrates that cigarette smoking accounts for this confounding bias. In addition, our population-specific data do not demonstrate significant differences in serum fatty acid composition, including ω-3 and ω-6 long chain polyunsaturated fatty acids, in Japanese patients with and without AMD. These results are consistent with the high proportion of smokers in aged Japanese men and the high fish oil intake in this population. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration.

PURPOSE: To determine whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and response to treatment with photodynamic therapy (PDT) for age-related macular degeneration (AMD) in a Japanese population. DESIGN: Prospective, case-control study. PARTICIPANTS: One hundred ten patients with exudative AMD treated by verteporfin PDT were recruited prospectively at the Department of Ophthalmology, Saitama Medical University Hospital, Saitama, Japan. METHODS: The patients were genotyped for 4 single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. MAIN OUTCOME MEASURES: The treatment outcomes and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS: Best-corrected visual acuity 1 year after PDT was significantly increased in patients with the HTRA1-rs11200638 GG genotype as compared with patients with the GA or AA genotypes (P = 2.9 × 10⁻², 7.0 × 10⁻4, respectively). The rate of recurrence in the 12-month period after PDT was also associated with HTRA1-rs11200638 genotype (P = 3.12 × 10⁻²). Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of the recurrence than patients with the GG genotype (P = 5.58 × 10⁻³). Significant differences were demonstrated in the mean time interval from the initial treatment to the time of recurrence for the genotypes of CFH-rs1410996/-rs2274700 (P = 8.50 × 10⁻³). CONCLUSIONS: The HTRA1-rs11200638 and CFH-rs1410996/-rs2274700 variants were associated with response to PDT in this study population. These variants may be used for genetic biomarkers to estimate visual outcomes and recurrences in the response to PDT with significant predictive power.

Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population.

PURPOSE: To describe phenotype and genotype characteristics of age-related macular degeneration (AMD) in Japanese patients. DESIGN: A case-control study. PARTICIPANTS: A total of 550 case-control samples composed of 408 consecutive AMD cases and 142 controls. METHODS: Clinical information assessing age, gender, affected eyes, fundus features, and fluorescein/indocyanine green angiograms were systematically evaluated. Four single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the complement factor H (CFH) gene, 1 SNP (rs11200638) in the high-temperature requirement factor A1 (HTRA1) gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were assessed using TaqMan technology. MAIN OUTCOME MEASURES: The clinical phenotype information and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS: Of Japanese patients with neovascular AMD (nAMD), 219 (58.7%) had typical nAMD and 154 (41.3%) had polypoidal choroidal vasculopathy (PCV). The frequency of bilateral exudative involvement was similar between typical nAMD (15.5%) and PCV (13.6%) (P = 0.613). Significant soft drusen were observed in the fellow eyes of 88 (47.6%) of 185 patients with unilateral typical nAMD and in 25 (18.8%) of 133 patients with unilateral PCV (P = 1.24x10(-7)). A serous pigment epithelium detachment was seen in 55 (25.1%) of 219 patients with typical nAMD and in 64 (41.6%) of 154 patients with PCV. A significant association was noted in CFH-rs800292, CFH-rs1410996, CFH-rs2274700, and HTRA1-rs11200638 with AMD development (P = 2.36x10(-5), 7.18x10(-5), 7.18x10(-5), 2.70x10(-7), respectively; population attributable risk = 57.3%, 57.8%, 57.8%, and 58.9%, respectively). We estimated the highest-risk group to have an approximately 70-fold greater risk of nAMD compared with the lowest-risk group when analyzing a combination of 4 SNPs in the CFH and HTRA1 genes. CONCLUSIONS: The Japanese AMD phenotype is characterized by a higher frequency of PCV, male predominance, and lower frequency of bilateral presentation compared with Caucasian AMD. Genotype analyses demonstrate a significant population attributable risk for SNPs in the CFH and HTRA1 genes and demonstrate joint effects for both genes. Gene variants in both CFH and HTRA1 contribute significantly to the AMD phenotype in a Japanese population.

Coding and noncoding variants in the CFH gene and cigarette smoking influence the risk of age-related macular degeneration in a Japanese population.

PURPOSE: Ethnic variation has been reported in age-related macular degeneration (AMD)-associated Y402H polymorphism in complement factor H (CFH). This variation is evident in the Japanese population. Recently a strong association between a novel single-nucleotide polymorphism (SNP; rs1410996) in the CFH gene and AMD has been identified in Caucasian patients. The present study was undertaken to investigate whether four coding and noncoding variants of the CFH gene, including rs1410996, are associated with AMD in native, unrelated Japanese patients. METHODS: A total of 188 patients with AMD and 139 control subjects without AMD were recruited for the study. Four SNPs (rs800292, rs1061170, rs1410996, and rs2274700) in the CFH gene were assessed by genotyping assay. The information regarding systemic conditions and lifestyle including smoking were documented in each subject by standardized questionnaire. RESULTS: The intronic SNP (rs1410996) and the synonymous SNP (rs2274700) were associated with a significant risk of AMD (P = 2.37 x 10(-5) and 3.52 x 10(-5), respectively). A significant association was also noted between a coding variant (rs800292, I62V) and AMD (P = 8.63 x 10(-6)). In contrast, the Y402H variant showed no significant association with AMD (P = 0.101). Two common haplotypes also demonstrated significant association with AMD (P = 1.08 x 10(-3) and 2.00 x 10(-5)). Among the environmental factors, smoking alone had a significant association with AMD (P = 1.17 x 10(-4)). CONCLUSIONS: Although the Y402H variant was not significantly associated with AMD, other coding and noncoding variants in the CFH gene including rs1410996 and smoking moderately influenced the risk of AMD in a Japanese population.

[Case of corneally displaced malignant conjunctival melanoma].

BACKGROUND: We studied the clinicopathologic characteristics in a patient with malignant conjunctival melanoma associated with corneal invasion. CASE: A 62-year-old man had a small melanocytic lesion of the inferior palpebral conjunctiva. Previously he had undergone excisional biopsy and was diagnosed as having melanocytic hyperplasia without cytological atypia at an other hospital. He developed recurrence and was referred to us. The pigmentary lesion was observed in the entire inferior palpebral conjunctiva. Biomicroscopic examination revealed that there was a granular pigment lesion in the cornea. The patient was diagnosed as having conjunctival melanoma with corneal invasion and treated with orbital exenteration and chemotherapy in our hospital. Clinicopathologic tests revealed malignant melanoma cells invading through the bulbar conjunctiva and into the cornea. Ultrastructural study by electron microscopy of the pigmented tumor cells in the cornea showed several lobations of the nuclei, a large active-appearing nucleolus, and an aberrant granular melanosomal morphology. CONCLUSIONS: The infiltration of palpebral malignant conjunctival melanoma was limited to the epidermis of the cornea.

A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 × 10-6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.

Promoter polymorphisms of the pigment epithelium-derived factor gene are associated with diabetic retinopathy.

Pigment epithelium-derived factor (PEDF or SERPINF1), a neuroprotective and anti-angiogenic factor, may play an important role in the pathogenesis of diabetic retinopathy (DR). In 416 patients with type 2 diabetes, four polymorphisms in the PEDF SNPs were identified, rs12150053 and rs12948385 in the promoter region, rs9913583 in the 5'-untranslated region, and rs1136287 (Met72Thr) in exon 3. Based on case-control studies, rs12150053 and rs12948385, but not rs9913583 and rs1136287, were significantly associated with DR. A logistic regression analysis revealed that the TC or CC genotype of rs12150053 was a significant risk factor for DR (odds ratio 2.40, p=0.0004). The GA or AA genotype of rs12948385 was also a significant risk factor for DR. In addition, a significant interaction between the vascular endothelial growth factor (VEGF) and PEDF SNPs in the susceptibility to DR was found. These results demonstrate that the PEDF gene, in cooperation with the VEGF gene, may contribute to the development of DR.