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Masahiro Miyake,
Kenji Yamashiro, Hideo Nakanishi,
Isao Nakata,
Yumiko Akagi-Kurashige,
Kyoko Kumagai,
Maho Oishi,
Akitaka Tsujikawa,
Muka Moriyama,
Kyoko Ohno-Matsui,
Manabu Mochizuki,
Nagahisa Yoshimura
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ABSTRACT: PURPOSE: We conducted a case-control study in a relatively large cohort of highly myopic patients to explore the genetic background of the occurrence of choroidal neovascularization (CNV) secondary to high myopia. METHODS: We evaluated 3 single nucleotide polymorphisms (SNPs) from 2 candidate genes: pigment epithelium-derived factor (PEDF) and complement factor I (CFI). The SNPs were selected based on previous reports. A total of 1082 unrelated highly myopic (i.e., axial length ≥ 26 mm in at least one eye) Japanese individuals with CNV (n = 478) and without CNV (n = 557) who were ≥50 years of age were genotyped by using the Taqman SNP assay. Multivariable logistic regression was conducted to adjust for age, sex, and axial length. RESULTS: Compared to individuals without CNV, subjects with CNV were significantly older (P < 0.01) and more likely to be female (P < 0.01), but they did not have a significantly different axial length (P = 0.50). We did not find an association between the 3 SNPs and the occurrence of CNV. However, a subanalysis using extremely myopic patients (case: control = 284:317) revealed a marginal association of rs12603825 in the PEDF gene (P = 0.045). The contribution of rs1136287 in CFI was not found in any analysis. CONCLUSIONS: We demonstrated a marginal association of the PEDF SNP, rs12603825, with myopic CNV in extremely myopic patients. A further study using a larger cohort might elucidate a significant association. Rs1136287 in CFI is less likely to be associated in Japanese individuals.
Investigative ophthalmology & visual science 05/2013; · 3.43 Impact Factor
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Masahiro Miyake,
Kenji Yamashiro, Hideo Nakanishi,
Isao Nakata,
Yumiko Akagi-Kurashige,
Akitaka Tsujikawa,
Muka Moriyama,
Kyoko Ohno-Matsui,
Manabu Mochizuki,
Ryo Yamada,
Fumihiko Matsuda,
Nagahisa Yoshimura
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ABSTRACT: To investigate whether genetic variations in the insulin-like growth factor 1 (IGF-1) gene are associated with high myopia in Japanese.
A total of 1,339 unrelated Japanese patients with high myopia (axial length ≥26 mm in both eyes) and two independent control groups were evaluated (334 cataract patients without high myopia and 1,194 healthy Japanese individuals). The mean axial length (mm±SD) in the case group was 29.18±1.85 mm, and the mean spherical equivalent (D±SD) of the phakic eyes was -12.69±4.54 D. We genotyped five tagging single nucleotide polymorphisms (SNPs) in IGF-1: rs6214, rs978458, rs5742632, rs12423791, and rs2162679. Chi-square tests for trend, multivariable logistic regression, and haplotype regression analysis were conducted.
We found no significant association between the IGF-1 SNPs and high or extreme myopia (axial length ≥28 mm in both eyes, 837 subjects) in the additive model, even when compared with the cataract and general population controls, with or without adjustments for age and sex. The evaluation using dominant and recessive models also did not reveal any significant associations. The haplotype analysis with a variable-sized sliding-window strategy also showed a lack of association of IGF-1 SNPs with high or extreme myopia.
The results of the present study using a Japanese subset do not support the proposal that the IGF-1 gene determines susceptibility to high or extreme myopia in Caucasians and Chinese. Further studies are needed to confirm our reports in other populations and to identify the underlying genetic determinants of these ocular pathological conditions.
Molecular vision 01/2013; 19:1074-81. · 2.20 Impact Factor
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ABSTRACT: To study the association of ARMS2 A69S genotype with the development of exudative age-related macular degeneration (AMD) in the unaffected fellow eye and to estimate the duration until the development of AMD in the second eye.
Retrospective cohort study.
We retrospectively reviewed 326 patients who had exudative AMD in at least 1 eye, genotyping of ARMS2 A69S, and a minimum follow-up of 2 years. Survival analysis and Cox proportional hazard regression analysis were used to examine the association between candidate factors and the duration until the development of AMD in the second eye.
One hundred nineteen patients (36.5%) had bilateral exudative AMD at the initial visit. A risk allele of ARMS2 A69S was more frequently seen in patients with bilateral AMD (P = .0270) than in those with unilateral AMD. Of the 207 unilateral AMD patients, 23 (11.1%) had AMD in the fellow eye after a mean duration of 56.3 ± 40.4 months. Fellow-eye involvement was associated with ARMS2 A69S genotype (hazard ratio [HR], 2.673; P = .0013), age (HR, 1.102; P = .0005), and smoking history (HR, 0.680; P = .3663). As HRs indicate, correlation of genotype (2.673) was as high as that of 10-year aging (1.102(10) = 2.641). Survival analysis revealed that patients with risk homozygous (TT) genotype had second-eye involvement significantly earlier than those with other genotypes (P = .0028). When the observation duration reached 120 months, second-eye involvement had developed in 50%, 6.6%, and 11.2% of the TT, GT, and GG cohorts, respectively.
ARMS2 A69S genotype is associated with second-eye involvement of exudative AMD and with the period between first- and second-eye involvements.
American journal of ophthalmology 07/2012; 154(3):542-548.e1. · 3.83 Impact Factor
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Yumiko Akagi-Kurashige,
Kyoko Kumagai,
Kenji Yamashiro, Hideo Nakanishi,
Isao Nakata,
Masahiro Miyake,
Akitaka Tsujikawa,
Muka Moriyama,
Kyoko Ohno-Matsui,
Manabu Mochizuki,
Ryo Yamada,
Fumihiko Matsuda,
Nagahisa Yoshimura
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ABSTRACT: To investigate a potential association between VEGF gene polymorphisms and the occurrence and/or the size of choroidal neovascularization (CNV) in highly myopic eyes.
In the case-control study for CNV occurrence, 327 highly myopic Japanese patients were enrolled. One hundred and eighty-four patients had CNV in at least one eye, and 143 did not have CNV in either eye. Of the 184 patients with CNV, 83 patients were used to evaluate an association with CNV size, and an additional 76 patients with CNV were used to confirm the association. We genotyped four tag single nucleotide polymorphisms (SNPs) and four functional SNPs previously reported to be correlated with VEGF gene expression to evaluate the associations of these eight SNPs with CNV occurrence and size. To confirm the association between CNV size and VEGF gene polymorphism, the associated SNP was genotyped in 76 additional patients with myopic CNV.
There was no significant association between the occurrence of myopic CNV and the SNPs in the VEGF gene (P > 0.16). Of the eight SNPs evaluated, however, rs2010963 showed significant association with CNV area (P = 0.0047). This association was successfully replicated in the additional 76 eyes with myopic CNV, and pooled analysis revealed significant association of rs2010963 with CNV size (P = 0.00078).
VEGF gene polymorphisms were not associated with CNV occurrence in highly myopic eyes but were significantly associated with the size of CNV, suggesting roles in the growth rather than the emergence of CNV.
Investigative ophthalmology & visual science 03/2012; 53(4):2349-53. · 3.43 Impact Factor
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ABSTRACT: To compare automated assessment of macular drusen delineated by the authors' originally developed algorithm on three-dimensional (3D) spectral-domain optical coherence tomography (SD-OCT) with the assessment by certified graders on color fundus photographs in nonneovascular age-related macular degeneration (AMD).
Automated assessment of macular drusen was performed using raster scan by 3D OCT scans in 18 eyes with nonneovascular AMD with at least one large druse (≥125 μm) and predominantly soft indistinct drusen. Drusen was defined as the regions that have the distance between the retinal pigment epithelium and calculated Bruch's membrane lines > predefined threshold distances. The agreement was assessed on maximum drusen size and drusen area within grid between 3D SD-OCT and color fundus photographs, and false-negative and false-positive drusen at each threshold distance.
There was agreement or agreement within one step in all eyes in maximum drusen size, and 15 (83.3%) of the eyes in the drusen area, except 6 pixels, regardless of threshold distances. However, the number of eyes with exact agreement in the drusen area increased when the threshold distances were smaller than 4 pixels. In the three cases with disagreement in the drusen area, false-negative drusen on 3D SD-OCT were characterized by being small in area and height.
Automated assessment of drusen parameters based on the authors' algorithm on 3D SD-OCT, which was limited by the poor detection ability of small drusen, showed good agreement with the assessment by certified graders on color fundus photography in these subjects.
Investigative ophthalmology & visual science 02/2012; 53(3):1576-83. · 3.43 Impact Factor
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Isao Nakata,
Kenji Yamashiro,
Ryo Yamada,
Norimoto Gotoh, Hideo Nakanishi,
Hisako Hayashi,
Yumiko Akagi-Kurashige,
Akitaka Tsujikawa,
Atsushi Otani,
Masaaki Saito,
Tomohiro Iida,
Akio Oishi,
Keitaro Matsuo,
Kazuo Tajima,
Fumihiko Matsuda,
Nagahisa Yoshimura
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ABSTRACT: To determine whether genetic variants in the complement component 2 and factor B gene (C2/CFB) locus are associated with the risk for typical age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV) in a Japanese population.
Four single nucleotide polymorphisms (SNPs) were genotyped across the C2/CFB locus of patients with typical AMD (n = 455) or PCV (n = 581) and of 865 controls. Differences in the observed genotypic distribution between the case and control groups were tested by logistic regression analysis for age and sex adjustments. Significant associations were confirmed using a second control group of 336 cataract patients. A further model adjusting for age-related maculopathy susceptibility 2 (ARMS2) A69S, complement factor H (CFH) I62V, age, sex and smoking status was performed, to confirm their independent association from other covariates.
C2 rs547154 and CFB rs541862 were significantly associated with typical AMD and PCV in this Japanese sample (P < 0.05). These two SNPs were also significantly associated with typical AMD and PCV in evaluation of the second control cohort (P < 0.05). Furthermore, an independent association of C2/CFB variants was found for both typical AMD and PCV with age, sex, smoking, and genetic background of ARMS2 A69S and CFH I62V (vs. typical AMD: P = 0.0073, odds ratio [OR] = 0.47; vs. PCV: P = 0.0083, OR = 0.53).
C2/CFB variants play a protective role in the risk of developing neovascular AMD and PCV in the Japanese.
Investigative ophthalmology & visual science 02/2012; 53(2):794-8. · 3.43 Impact Factor
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Masahiro Miyake,
Kenji Yamashiro, Hideo Nakanishi,
Isao Nakata,
Yumiko Akagi-Kurashige,
Akitaka Tsujikawa,
Muka Moriyama,
Kyoko Ohno-Matsui,
Manabu Mochizuki,
Ryo Yamada,
Fumihiko Matsuda,
Nagahisa Yoshimura
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[hide abstract]
ABSTRACT: The objective of this study was to investigate whether genetic variations in the paired box 6 (PAX6) gene are associated with high myopia in Japanese subjects.
A total of 1,307 unrelated Japanese patients with high myopia (axial length ≥26 mm in both eyes) and two independent control groups were evaluated (333 cataract patients without high myopia and 923 age-matched healthy Japanese individuals). We genotyped three tag single-nucleotide polymorphisms (SNPs) in PAX6: rs2071754, rs644242, and rs3026354. These SNPs provided 100% coverage of all phase II HapMap SNPs within the PAX6 region (minor allele frequency ≥0.10; r(2) threshold: 0.90). Chi-square tests for trend and multivariable logistic regression were conducted.
Genotype distributions in the three SNPs were in accordance with the Hardy-Weinberg equilibrium. After adjusting for age and sex, evaluation of cataract control showed a marginal association with high myopia in rs644242 (odds ratio [95% confidence interval]=0.69 [0.49-0.96], p=0.026), and a significant association was observed in healthy Japanese controls (0.79 [0.66-0.96], p=0.015). We pooled two control cohorts to evaluate the association. This analysis revealed a strong association between rs644242 and high myopia (0.78 [0.65-0.92], p=0.0045). The rs644242 A allele was a protective allele for development of high myopia. Subanalysis also revealed that rs644242 was significantly associated with extreme high myopia (0.78 [0.64-0.95], p=0.0165). The other two SNPs did not show a significant association with this condition.
The current study showed a significant association of PAX6 with high and extreme myopia in Japanese participants. The A allele of rs644242 is a protective allele.
Molecular vision 01/2012; 18:2726-35. · 2.20 Impact Factor
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ABSTRACT: To visualize the macular ganglion cell layer (GCL) and measure its thickness in normal eyes and eyes with preperimetric glaucoma, using speckle noise-reduced spectral domain optical coherence tomography (SD-OCT).
Retrospective consecutive case series.
Thirty-seven eyes of 37 patients with preperimetric glaucoma and 39 normal eyes of 39 volunteers.
Vertical and horizontal SD-OCT B-scan images were acquired with minimal speckle noise by using eye-tracking to obtain and average 50 B-scans at each identical location of interest. B-scan images were manually analyzed for GCL, retinal nerve fiber layer (RNFL), and inner plexiform layer shapes and thicknesses in the macula.
Macular GCL images and thickness in normal eyes and in eyes with preperimetric glaucoma.
The macular GCL was clearly seen on speckle noise-reduced SD-OCT images in normal eyes and eyes with preperimetric glaucoma. In each eye with preperimetric glaucoma, thinning of the macular GCL was visually apparent, particularly on vertical scans. The mean regional macular GCL was most severely thinned in the inferior perifoveal region, where its thickness was <70% of its normal thickness in 30 (81.1%) of the 37 eyes and <50% of its normal thickness in 13 (35.1%) of the 37 eyes. When the sensitivity and specificity for detecting abnormal thinning (outside the lower limit of 99% confidence interval [CI] for the means in the 39 normal eyes) in at least one 0.5-mm segment or sector were compared, the macular GCL on vertical B-scans exhibited higher sensitivity (81.1%) than the other layers on vertical B-scans (99% CI, 5.4%-59.5%; P = 0.00075-0.02100), the macular GCL (99% CI, 40.5%; P = 0.00027) on horizontal B-scans, the other layers (99% CI, 5.4%-48.6%; P<0.00048-0.00400) on horizontal B-scans, and circumpapillary RNFL automatically measured on SD-OCT (54.1%; P = 0.021), and scanning laser polarimetry with variable corneal compensation (24.3%; P = 0.00095). All the macular layers on both the vertical and horizontal B-scans and circumpapillary RNFL thickness exhibited comparable specificity (91.4-100.0%, statistically not different).
Speckle noise-reduced SD-OCT imaging allowed clear visualization and measurement of the macular GCL, which was severely thinned in eyes with preperimetric glaucoma.
Proprietary or commercial disclosure may be found after the references.
Ophthalmology 09/2011; 118(12):2414-26. · 5.45 Impact Factor
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ABSTRACT: To investigate the association between the vascular endothelial growth factor (VEGF) gene and response to either intravitreal bevacizumab (IVB) or photodynamic therapy with intravitreal triamcinolone acetonide and IVB (triple therapy) for neovascular age-related macular degeneration (AMD).
The study consisted of 94 patients with neovascular AMD who underwent IVB and 79 patients with neovascular AMD who underwent triple therapy. Genotypes were determined for four selected tagging single-nucleotide polymorphism (SNP)s of the VEGF gene.
Of the four SNPs studied, one SNP (rs699946) was associated significantly with visual acuity (VA) changes 12 months after treatment-irrespective of whether they received IVB alone (P = 0.044) or triple therapy 0.010). Baseline VA was not significantly different among the three genotypes of rs699946 in either treatment group. There were no significant differences in the number of treatments, incidence of recurrence, or the period until the recurrence according to VEGF rs699946 genetic variant.
The VEGF gene SNP rs699946 was associated with response to IVB alone and to triple therapy in this study. The G allele in SNP rs699946 can thus be applied as a marker for better visual prognosis in patients with neovascular AMD who receive either IVB or triple therapy.
Japanese Journal of Ophthalmology 07/2011; 55(5):435-43. · 0.92 Impact Factor
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ABSTRACT: To compare retinal nerve fiber layer (RNFL) defects on fundus photographs with circumpapillary RNFL (cpRNFL) thinning or disruption on images obtained by speckle-noise-reduced spectral-domain optical coherence tomography (enhanced SD OCT), single-scan SD OCT, and single-scan time-domain OCT (TD OCT).
Retrospective, comparative case series.
Forty-four eyes of 44 patients with open-angle glaucoma with localized, wedge-shaped RNFL defects on red-free photographs and 35 normal eyes of 35 volunteers.
Cross-sectional images of the cpRNFL and cpRNFL thinning, compared with the confidence interval limit of the normative database where the RNFL defect was photographically identified, were compared between the 3 types of OCT instruments: enhanced SD OCT (SD OCT with eye tracking and averaging of 16 images at the same location to reduce speckle noise; Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany), single-scan SD OCT (RTVue-100; Optovue, Fremont, CA), and single-scan TD OCT (Stratus; Carl Zeiss-Meditec, Dublin, CA).
Cross-sectional images of localized RNFL defects on red-free fundus photographs, sensitivity for detecting the photographic RNFL defect, and sensitivity and specificity for detecting glaucoma as having at least 1 abnormally thinned sector on the cpRNFL thickness map on OCT.
Among the 44 eyes with glaucoma, 65 RNFL defects were identified on red-free fundus photographs. The cpRNFL boundaries were clearer on enhanced SD OCT images than on single-scan SD OCT or TD OCT images, particularly in regions corresponding to the RNFL defects. Enhanced SD OCT revealed various degrees of cpRNFL thinning, and disruption of cpRNFL reflectivity was seen in the same location as the photographic RNFL defect for 23 (35.4%) of the 65 RNFL defects. The RNFL defects were significantly less likely to be detected by single-scan TD OCT or SD OCT (P = 0.002 and P = 0.006, respectively) when the RNFL was not disrupted. Enhanced SD OCT was more sensitive in detecting the RNFL defects that were not disrupted compared with single-scan TD OCT (P<0.0001) or SD OCT (P<0.0001). Enhanced SD OCT had better sensitivity and specificity for detecting glaucoma compared with single-scan TD OCT or SD OCT (sensitivity, P = 0.006 and P = 0.001; specificity, P = 0.001 and P = 0.004, respectively).
These results suggest that speckle-noise reduction can improve the detection of photographic RNFL defects in which cpRNFL reflectivity on OCT images is not disrupted.
Proprietary or commercial disclosure may be found after the references.
Ophthalmology 06/2011; 118(6):1038-48. · 5.45 Impact Factor
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Hisako Hayashi,
Kenji Yamashiro, Hideo Nakanishi,
Isao Nakata,
Yumiko Kurashige,
Akitaka Tsujikawa,
Muka Moriyama,
Kyoko Ohno-Matsui,
Manabu Mochizuki,
Mineo Ozaki,
Ryo Yamada,
Fumihiko Matsuda,
Nagahisa Yoshimura
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ABSTRACT: To investigate whether there are associations of genetic variations in chromosome 15q14 and 15q25, recently shown to confer risk of refractive error and myopia in Caucasians, with high myopia in Japanese.
A total of 1125 unrelated Japanese patients with high myopia and two independent control groups were evaluated (366 cataract patients without high myopia and 929 healthy Japanese patients). The four single nucleotide polymorphisms (SNPs) rs634990 and rs524952 at 15q14 and rs8027411 and rs17175798 at 15q25 were genotyped.
A significant association with high myopia was observed in 15q14 (P = 0.0035 for rs634990 and P = 0.0017 for rs524952 when evaluated with cataract controls and P = 1.91 × 10(-6) for rs634990 and P = 8.78 × 10(-7) for rs524952 with healthy Japanese controls). When evaluated with cataract controls, the odds ratios (95% confidence intervals) were 1.30 (1.10-1.53) for rs634990 C allele and 1.32 (1.11-1.56) for rs524952 A allele. The population attributable risks were 0.29 and 0.30, respectively. The SNPs in 15q25 did not show a significant association with high myopia when evaluated with cataract control (P > 0.42), while it showed a weak association when evaluated with healthy Japanese controls (P = 0.031 for rs8027411 and P = 0.047 for rs17175798) with odds ratios of 1.17 (1.03-1.33) for rs8027411 T allele and 1.15 (1.02-1.31) for rs17175798 C allele.
These findings suggest that a region in 15q14 is susceptibility loci for high myopia. This locus harbor susceptibility genes for not only common myopia but also for high myopia. The 15q25 locus might also have association to myopia.
Investigative ophthalmology & visual science 03/2011; 52(7):4853-8. · 3.43 Impact Factor
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Isao Nakata,
Kenji Yamashiro,
Ryo Yamada,
Norimoto Gotoh, Hideo Nakanishi,
Hisako Hayashi,
Akitaka Tsujikawa,
Atsushi Otani,
Sotaro Ooto,
Hiroshi Tamura,
Masaaki Saito,
Kuniharu Saito,
Tomohiro Iida,
Akio Oishi,
Yasuo Kurimoto,
Fumihiko Matsuda,
Nagahisa Yoshimura
[show abstract]
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ABSTRACT: To investigate whether photodynamic therapy (PDT) outcomes of polypoidal choroidal vasculopathy (PCV) are related to baseline clinical characteristics, smoking history, or genetic factors by analyzing the retreatment-free period after the first PDT.
Retrospective cohort study.
The study consisted of 167 patients with PCV who underwent PDT as their first treatment.
We targeted 638 single nucleotide polymorphisms (SNPs) in 42 possible susceptible genes for age-related macular degeneration to evaluate their relation to the effectiveness of PDT for PCV. For this evaluation, we used 2 methods: (1) survival analysis, with the retreatment-free period as the target; and (2) logistic regression test between the need for additional therapy within 3 months after the first PDT and the genotypes, with age, gender, smoking status, and greatest linear dimension (GLD) at baseline as covariates. The contributions of smoking status and GLD at baseline for the retreatment-free period also were evaluated. Contributions of these factors to visual prognosis were evaluated for 1 year after PDT.
Retreatment-free period after the first PDT for PCV. Secondary outcome measures included correlation of the susceptible factor to the retreatment requirement within the 3-month follow-up and the mean visual acuity change.
In survival analyses, SERPINF1 rs12603825 showed a significant association with the retreatment-free period after the first PDT; those patients homozygous for the minor allele A of rs12603825 received additional treatment after PDT within significantly shorter times than those with other genotypes (P = 0.0038). There was no significant difference in the retreatment-free period between baseline GLD and smoking status. Retreatment within 3 months was required significantly more in patients with the AA genotype, even after taking into consideration the effect of clinical characteristics (age, gender), baseline PCV lesion size, and smoking status (P = 0.0027). Furthermore, patients with the AA genotype showed significantly worse visual prognosis after PDT (P = 0.013).
Pigment epithelium-derived factor (SERPINF1 or PEDF) polymorphisms may influence the initial response to and visual prognosis after PDT for PCV. Our findings may lead to understanding the pathogenesis of PCV and modification of the effects of PDT.
Ophthalmology 03/2011; 118(7):1408-15. · 5.45 Impact Factor
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ABSTRACT: To investigate the progression of vascular lesions of polypoidal choroidal vasculopathy (PCV) as viewed with indocyanine green angiography and the visual prognosis of these eyes.
Retrospective case study.
We reviewed retrospectively the medical records of 88 consecutive patients (88 eyes) with PCV who had been examined with indocyanine green angiography for more than 2 years.
Depending on the initial area of the vascular lesion, eyes were divided into smaller PCV (baseline area of lesion being < 1 disc area [DA], n = 22) and larger PCV (baseline area of lesion being ≥ 1 DA, n = 66). In larger PCV, the mean area of the lesion progressed significantly from 6.49 ± 8.96 mm(2) to 16.27 ± 14.19 mm(2) (P < .0001) with marked deterioration of visual acuity (P < .0001) during follow-up. In contrast, smaller PCV often showed minimal progression of the lesion, only limited exudative change, and the eyes maintained their initially good vision to the final visit. Smaller PCV lesions rarely progressed to extensive PCV lesions. Severe vision-threatening complications (ie, suprachoroidal hemorrhage, vitreous hemorrhage, and tears of the retinal pigment epithelium) were seen only in eyes with larger PCV, and in studying single nucleotide polymorphisms A69S of ARMS2 genes, there was a significant difference in T allele frequency between individuals with smaller PCV and those with larger PCV (20.2% vs 79.8%; P = .0235).
PCV with small vascular lesions shows minimal progression and no vision-threatening complications, and these eyes often maintain good visual acuity for a long time.
American journal of ophthalmology 03/2011; 151(6):961-972.e1. · 3.83 Impact Factor
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Yi-Ju Li,
Liang Goh,
Chiea-Chuen Khor,
Qiao Fan,
Miao Yu,
Siyu Han,
Xueling Sim,
Rick Twee-Hee Ong,
Tien-Yin Wong,
Eranga Nishanthie Vithana,
Eric Yap, Hideo Nakanishi,
Fumihiko Matsuda,
Kyoko Ohno-Matsui,
Nagahisa Yoshimura,
Mark Seielstad,
E-Shyong Tai,
Terri L Young,
Seang-Mei Saw
[show abstract]
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ABSTRACT: To determine susceptibility genes for high myopia in Singaporean Chinese.
A meta-analysis of 2 genome-wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese.
Two independent datasets of Singaporean Chinese individuals aged 10 to 12 years (Singapore Cohort Study of the Risk factors for Myopia [SCORM]: cases = 65, controls = 238) and more than 21 years (Singapore Prospective Study Program [SP2]: cases = 222, controls = 435) for GWA studies, and a Japanese dataset aged more than 20 years (cases = 959, controls = 2128) for replication.
Genomic DNA samples from SCORM and SP2 were genotyped using various Illumina Beadarray platforms (>HumanHap 500). Single-locus association tests were conducted for each dataset with meta-analysis using pooled z-scores. The top-ranked genetic markers were examined for replication in the Japanese dataset. Fisher P was calculated for the combined analysis of all 3 cohorts.
High myopia, defined by spherical equivalent (SE) ≤ -6.00 diopters (D); controls defined by SE between -0.50 and +1.00 D.
Two SNPs (rs12716080 and rs6885224) in the gene CTNND2 on chromosome 5p15 ranked top in the meta-analysis of our Chinese datasets (meta P = 1.14 × 10(-5) and meta P = 1.51 × 10(-5), respectively) with strong supporting evidence in each individual dataset analysis (max P = 1.85 × 10(-4) in SCORM: max P = 8.8 × 10(-3) in SP2). Evidence of replication was observed in the Japanese dataset for rs6885224 (P = 0.035, meta P of 3 datasets: 7.84 × 10(-6)).
This study identified a strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15.
Ophthalmology 02/2011; 118(2):368-75. · 5.45 Impact Factor
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Isao Nakata,
Kenji Yamashiro,
Ryo Yamada,
Norimoto Gotoh, Hideo Nakanishi,
Hisako Hayashi,
Akitaka Tsujikawa,
Atsushi Otani,
Masaaki Saito,
Tomohiro Iida,
Akio Oishi,
Keitaro Matsuo,
Kazuo Tajima,
Fumihiko Matsuda,
Nagahisa Yoshimura
[show abstract]
[hide abstract]
ABSTRACT: Recently, a complement component 1 inhibitor (SERPING1) gene polymorphism was identified as a novel risk factor for age-related macular degeneration (AMD) in Caucasians. We aimed to investigate whether variations in SERPING1 are associated with typical AMD or with polypoidal choroidal vasculopathy (PCV) in a Japanese population.
We performed a case-control study in a group of Japanese patients with typical AMD (n = 401) or PCV (n = 510) and in 2 independent control groups--336 cataract patients without age-related maculopathy and 1,194 healthy Japanese individuals. Differences in the observed genotypic distribution between the case and control groups were tested using chi-square test for trend. Age and gender were adjusted using logistic regression analysis.
We targeted rs2511989 as the haplotype-tagging single nucleotide polymorphism (SNP) for the SERPING1 gene, which was reported to be associated with the risk of AMD in Caucasians. Although we compared the genotypic distributions of rs2511989 in typical AMD and PCV patients against 2 independent control groups (cataract patients and healthy Japanese individuals), SERPING1 rs2511989 was not significantly associated with typical AMD (P = 0.932 and 0.513, respectively) or PCV (P = 0.505 and 0.141, respectively). After correction for age and gender differences based on a logistic regression model, the difference in genotypic distributions remained insignificant (P>0.05). Our sample size had a statistical power of more than 90% to detect an association of a risk allele with an odds ratio reported in the original studies for rs2511989 for developing AMD.
In the present study, we could not replicate the reported association between SERPING1 and either neovascular AMD or PCV in a Japanese population; thus, the results suggest that SERPING1 does not play a significant role in the risk of developing AMD or PCV in Japanese.
PLoS ONE 01/2011; 6(4):e19108. · 4.09 Impact Factor
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Kenji Yamashiro,
Keisuke Mori,
Isao Nakata,
Takashi Tsuchihashi,
Kuniko Horie-Inoue, Hideo Nakanishi,
Akitaka Tsujikawa,
Masaaki Saito,
Tomohiro Iida,
Ryo Yamada,
Fumihiko Matsuda,
Satoshi Inoue,
Takuya Awata,
Shin Yoneya,
Nagahisa Yoshimura
[show abstract]
[hide abstract]
ABSTRACT: To see if there is an association in Japanese between elastin gene (ELN) polymorphisms and neovascular age-related macular degeneration (AMD) or its subtypes, typical AMD (tAMD) and polypoidal choroidal vasculopathy (PCV).
The authors genotyped five single nucleotide polymorphisms (SNPs), rs2301995, rs2856728, rs868005, rs884843, and rs13239907, at Kyoto University and Saitama Medical University. A case-control study was performed on 1296 patients with AMD and 478 controls.
A statistically significant association was detected between the rs2301995 SNP and AMD (P = 0.018). Furthermore, subtype analysis revealed a significant association of rs2301995 with tAMD (P = 0.0018), but not with PCV. The genotype distribution of rs2301995 also differed significantly between tAMD and PCV (P = 0.00030). The trend in genotype distribution of rs2301995 was similar between the Kyoto and the Saitama studies. The A allele frequency was higher in tAMD, whereas it was similar in PCV and in controls, which is opposite to that reported in a previous study that the A allele frequency is higher in PCV, whereas it is similar in tAMD and in controls. Haplotype analysis also showed that the ELN polymorphism is significantly associated with tAMD (P = 0.0055), but not with PCV.
ELN is associated with AMD in Japanese. Furthermore, the findings suggest that ELN is a susceptibility gene for tAMD but not for PCV, which is opposite to that reported in a previous study that ELN is the susceptibility gene for PCV but not for tAMD.
Investigative ophthalmology & visual science 01/2011; 52(12):8780-4. · 3.43 Impact Factor
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Hideo Nakanishi,
Kenji Yamashiro,
Ryo Yamada,
Norimoto Gotoh,
Hisako Hayashi,
Isao Nakata,
Masaaki Saito,
Tomohiro Iida,
Akio Oishi,
Yasuo Kurimoto,
Keitaro Matsuo,
Kazuo Tajima,
Fumihiko Matsuda,
Nagahisa Yoshimura
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ABSTRACT: To investigate whether the major genetic and environmental risk factors of age-related macular degeneration (AMD)-CFH Y402H and LOC387715 A69S and cigarette smoking-are also associated with polypoidal choroidal vasculopathy (PCV) and whether the associations of CFH Y402H and LOC387715 A69S with PCV are modified by smoking.
Three hundred seventy-five Japanese patients with PCV and 847 Japanese who served as population-based control subjects, all ≥55 years of age, were studied. CFH Y402H (rs1061170) and LOC387715 A69S (rs10490924) were genotyped with a single-nucleotide polymorphism (SNP) assay. An unconditional logistic regression model was used to analyze the association between age, sex, smoking status, CFH Y402H, LOC387715 A69S, and PCV. The synergy index (SI) was measured to assess gene-smoking and gene-gene interaction as a departure from additivity.
CFH Y402H, LOC3387715 A69S, and cigarette smoking status were all significantly associated with PCV; for CFH Y402H, the adjusted odds ratio (OR) for the number of copies of the allele was 1.63 (95% confidence interval [CI], 1.12-2.36; P < 0.05); for LOC387715 A69S, the adjusted OR was 2.26 (95% CI, 1.83-2.78; P < 0.0001); and for smoking status (ever versus never smoked), the adjusted OR was 1.45 (95% CI, 1.00-2.10; P < 0.05). The joint effect of CFH Y402H and smoking was significantly greater than the additive scale, with an SI of 2.41 (95% CI, 1.14-5.10).
CFH Y402H and LOC387715 A69S are both significantly associated with PCV. Cigarette smoking is an environmental risk factor for PCV. The findings suggest interactions between CFH 402H and cigarette smoking in PCV.
Investigative ophthalmology & visual science 12/2010; 51(12):6183-7. · 3.43 Impact Factor
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Hisako Hayashi,
Kenji Yamashiro,
Norimoto Gotoh, Hideo Nakanishi,
Isao Nakata,
Akitaka Tsujikawa,
Atsushi Otani,
Masaaki Saito,
Tomohiro Iida,
Keitaro Matsuo,
Kazuo Tajima,
Ryo Yamada,
Nagahisa Yoshimura
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ABSTRACT: To seek an association in Japanese individuals between the CFH polymorphisms Y402H and I62V and the ARMS2 polymorphism A69S and age-related macular degeneration (AMD) or its three subtypes: typical (t)AMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP).
The three polymorphisms were genotyped in a case-control study of 1351 control subjects and 962 patients with AMD.
The three polymorphisms correlated with AMD (Y402H, P = 1.54 × 10(-6); I62V, P =1.94 × 10(-29); and A69S, P = 9.56 × 10(-43)). The I62V and A69S polymorphisms were associated with all three subtypes: tAMD (P = 3.74 × 10(-18) and 1.37 × 10(-35), respectively), PCV (P = 3.18 × 10(-19) and 3.96 × 10(-18), respectively), and RAP (P = 0.034 and 2.49 × 10(-18), respectively). Y402H was associated with tAMD (P = 3.00 × 10(-5)) and with PCV (P = 9.73 × 10(-5)), but no association was found with RAP, possibly because of the small sample size and the rare minor allele. The risk allele contribution of A69S was stronger for RAP than for tAMD or PCV and was stronger for tAMD than for PCV.
CFH Y402H is associated with AMD, tAMD, and PCV, whereas I62V is associated with all three subtypes. ARMS2 A69S has a strong association with all three subtypes, with the association being strongest for RAP and weakest for PCV. PCV and RAP may thus be subtypes of AMD that are genetically distinct from tAMD.
Investigative ophthalmology & visual science 11/2010; 51(11):5914-9. · 3.43 Impact Factor
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ABSTRACT: To compare the genomic contribution of the ARMS2/HTRA1 region of chromosome 10q26 to typical neovascular age-related macular degeneration (nAMD) (also known as typical exudative AMD) and to polypoidal choroidal vasculopathy (PCV) METHODS: DNA samples were prepared from 84 patients with typical nAMD, 181 patients with PCV, and 276 control participants. All of the 18 haplotype-tagging single-nucleotide polymorphisms (SNPs) derived from the HapMap data and the potential functional variant, rs11200638, which extended the ARMS2/HTRA1 region by 85.2 kb, were genotyped. Associations were tested using single-SNP and haplotype analyses.
Statistically significant associations were found for six of the 19 SNPs with both typical nAMD and PCV (P < 1 × 10(-3)), peaking at a segment containing three of the SNPs: rs3793917, rs10490924, and rs11200638 (P < 10(-7)). Six common haplotypes were inferred from the nine SNPs spanning 33 kb, which included the six SNPs associated with both phenotypes. Among the six common haplotypes, one showed a positive association with typical nAMD, and two, including the one mentioned above, were associated with PCV. In addition, they corresponded to the risk alleles rs10490924 and rs11200638.
The association pattern and haplotype estimation in the ARMS2/HTRA1 region of Japanese patients with PCV were very similar to those of Japanese patients with typical nAMD. The polymorphisms responsible for nAMD and PCV may be located in this region or in the strong linkage disequilibrium of rs10490924 and rs11200638.
Japanese Journal of Ophthalmology 11/2010; 54(6):609-14. · 0.92 Impact Factor
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ABSTRACT: To examine the relationship between retinal sensitivity and morphologic changes in the macular area of eyes with confluent soft drusen.
We retrospectively reviewed the medical records of the 21 consecutive patients (22 eyes) who had confluent soft drusen in the macular area. Using spectral-domain optical coherence tomography, a 6 x 6-mm area of each macula was examined with 256 sequential horizontal scans. Microperimetry in the macular area was carried out using the Micro Perimeter 1.
Spectral-domain optical coherence tomography images showed that protrusion of the retinal pigment epithelium (RPE) corresponded to the site of the confluent soft drusen. In addition, irregularities of the reflective line of the junction between inner and outer segments (IS/OS) of the photoreceptors were noted in 17 (77.3%) eyes. These irregularities were seen in the area with the protrusion of RPE. At 510 (68.1%) of 748 points with an intact retina, retinal sensitivity was 14 decibels or better. However, a retinal sensitivity of 14 decibels or better was obtained at 38.9% of points in irregular RPE with an intact IS/OS line, but at only 15.2% of points with an irregular IS/OS line. The mean retinal sensitivities within the area of irregular RPE with an intact IS/OS line, or in areas with an irregular IS/OS line, respectively, were significantly lower than that of intact retina (P < 0.0001).
Eyes with confluent soft drusen often show focal areas with reduced retinal function, areas that are consistent with irregularity of the RPE or of the IS/OS line.
Clinical and Experimental Ophthalmology 07/2010; 38(5):483-8. · 1.98 Impact Factor
