November 2011
Volume 52, Issue 12
Free
Retina  |   November 2011
Association of Elastin Gene Polymorphism to Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy
Author Affiliations & Notes
  • Kenji Yamashiro
    From the Department of Ophthalmology and
  • Keisuke Mori
    the Department of Ophthalmology,
  • Isao Nakata
    From the Department of Ophthalmology and
    the Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan;
  • Takashi Tsuchihashi
    the Department of Ophthalmology,
  • Kuniko Horie-Inoue
    the Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, and
  • Hideo Nakanishi
    From the Department of Ophthalmology and
    the Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan;
  • Akitaka Tsujikawa
    From the Department of Ophthalmology and
  • Masaaki Saito
    the Department of Ophthalmology, Fukushima Medical University, Fukushima, Japan.
  • Tomohiro Iida
    the Department of Ophthalmology, Fukushima Medical University, Fukushima, Japan.
  • Ryo Yamada
    the Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan;
  • Fumihiko Matsuda
    the Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan;
  • Satoshi Inoue
    the Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, and
  • Takuya Awata
    the Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical University, Iruma, Saitama, Japan; and
  • Shin Yoneya
    the Department of Ophthalmology,
  • Nagahisa Yoshimura
    From the Department of Ophthalmology and
  • Corresponding author: Kenji Yamashiro, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Kawahara, Shogoin, Sakyo, Kyoto 606-8507, Japan; [email protected]
Investigative Ophthalmology & Visual Science November 2011, Vol.52, 8780-8784. doi:https://doi.org/10.1167/iovs.11-8205
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      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; Association of Elastin Gene Polymorphism to Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(12):8780-8784. https://doi.org/10.1167/iovs.11-8205.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose.: 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).

Methods.: 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.

Results.: 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.

Conclusions.: 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.

Neovascular age-related macular degeneration (AMD) is divided into polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation, and typical age-related macular degeneration (tAMD) that includes predominantly classic choroidal neovascularization (CNV) type, minimally classic CNV type, and occult with no classic CNV type. Differences between tAMD and PCV have been investigated for more than a decade. Although PCV is regarded as a subtype of AMD, its prognosis has been reported to be better than that of tAMD. 1,2 Furthermore, the response to treatment differs between tAMD and PCV. It has been shown that photodynamic therapy is more effective for PCV than that for tAMD. 3 5 In contrast, anti–vascular endothelium growth factor (VEGF) treatment just barely inactivates the polypoidal lesions of PCV, although it works well on the CNV associated with tAMD. 6 9 The prevalence of PCV and tAMD also differs depending on ethnicity. In Caucasians, PCV is seen in only 8–13% of neovascular AMD, 2 whereas it has been shown that 41.3–54.7% of neovascular AMD in Japanese patients have PCV. 10,11 These differences suggest genetic background differences in the development of tAMD and PCV. 
Susceptibility genes for AMD have been investigated intensely, and evidence has shown that the CFH gene and the ARMS2/HTRA1 gene are associated with AMD, tAMD, and PCV. 12 18 We have recently shown that the association of the ARMS2 gene is stronger for tAMD than for PCV, whereas the association of the CFH gene is similar between tAMD and PCV. 19 Discovery of a susceptibility gene associated only with tAMD but not with PCV, or vice versa, would deepen our understanding of the difference in pathogenesis between tAMD and PCV. 
Kondo and colleagues 20 evaluated five tag SNPs of the elastin gene (ELN) in Japanese, and showed that its polymorphism is associated with PCV but not with tAMD. Although they discussed the possibility that they might have underestimated the association with tAMD because of a type I error due to low samples sizes (n = 285), ELN might explain the different mechanisms involved in the development of tAMD and PCV. In Caucasians, however, it has been shown that ELN is not associated with PCV or AMD. 21,22  
Bruch's membrane is an elastin-rich extracellular matrix between retinal pigment epithelium and choroidal capillaries, whose defect can lead to CNV formation. Elastin polymerization deficit has been shown to lead to larger CNV in laser-induced CNV in mouse. 23 Furthermore, histophathologic studies showed disruption of the elastic layer of polypoidal vessels in PCV. Evaluation of elastin in CNV development would lead to more precise understanding of the difference between tAMD and PCV. 24,25 In the present study we evaluated the five tag SNPs of ELN at Kyoto University and, separately, at Saitama University, using the same probes to examine the association of ELN to AMD and to its subtypes tAMD and PCV in a relatively large cohort (n = 1774). 
Materials and Methods
This study was performed in accordance with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board/Ethics Committee of Kyoto Graduate School of Medicine, Kyoto, Japan, and by the Ethics Committee of Saitama Medical University, Saitama, Japan. Written informed consent was obtained from each patient. 
In all, 926 patients with neovascular AMD and 336 patients with cataract but no AMD selected as control were recruited from the Department of Ophthalmology at Kyoto University Hospital and from the Ophthalmology Department at Fukushima Medical University Hospital. Of the 926 patients, 408 had tAMD and 518 had PCV. A total of 142 control subjects and 370 patients with neovascular AMD, including 216 with tAMD and 154 with PCV, were recruited from Saitama Medical University Hospital. All subjects in the present study were unrelated and all were of Japanese descent. The diagnosis of PCV was based on indocyanine green angiography, which showed a branching vascular network that terminated in polypoidal swelling. Typical AMD showed classic CNV, occult CNV, or both. All diagnoses in the Kyoto study and the Saitama study were made by three retina specialists at each facility using fundus photograph, fluorescein and indocyanine green angiography, and optical coherence tomography; a fourth specialist was called on when the subtype classification could not be decided on by the initial three reviewers. Less than 5% of the diagnosis was made with the help of the fourth specialist. 
Genomic DNAs were prepared from peripheral blood using a DNA extraction kit (QuickGene-610L; Fujifilm, Minato, Tokyo, Japan, or Wizard Genomic DNA Purification Kit; Promega, Madison, WI). Tag SNPs were selected by use of a commercial database (HapMap database phase 2 release 22) by the tagger pairwise method with an R 2 cutoff of 0.8 and minor allele frequency (MAF) cutoff of 0.2, which included the five SNPs (rs2301995, rs2856728, rs868005, rs884843, and rs13239907) that were previously examined, 20,21 and were genotyped using an SNP assay (TaqMan, with the ABI PRISM 7700 system or 7000 system; Applied Biosystems, Foster City, CA). Mean ages were compared using ANOVA with post hoc comparisons tested by the Scheffé procedure. Allele frequency and sex ratio were compared with the χ2 test and the genotype distribution was compared with the χ2 test for trend or its exact counterpart. Age and sex differences were adjusted with logistic regression analysis software (R software, provided in the public domain by the R Foundation for Statistical Computing, Vienna, Austria, available at http://www.r-project.org/) by fitting the number of minor allele carried as an ordinal covariate, and age and sex as continuous and categorical covariates. Values of P < 0.05 were considered to be statistically significant. 
Results
Demographics of the study population are shown in Table 1. The mean ages and sex ratios were significantly different between controls and cases at each facility. Table 2 shows the genotype distributions of rs2301995, rs2856728, rs868005, rs884843, and rs13239907 in both the Kyoto study and the Saitama study. Since the genotype frequencies were not significantly different between the Kyoto study and the Saitama study, we pooled the data to evaluate the association of the five SNPs to AMD, tAMD, and PCV. 
Table 1.
 
Characteristics of Study Population
Table 1.
 
Characteristics of Study Population
Factor Kyoto Saitama
Controls tAMD PCV Controls tAMD PCV
Number 336 408 518 142 216 154
Mean age ± SD, y 74.2 ± 8.4* 77.7 ± 8.4* 75.1 ± 8.5* 68.4 ± 9.8† 72.7 ± 8.7† 71.8 ± 7.8†
Sex, male/female 142/194‡ 293/115‡ 381/137‡ 74/68‡ 158/58‡ 122/32‡
Table 2.
 
Genotype Distribution of ELN Gene SNPs in Control Subjects and in Patients with AMD, tAMD, or PCV in Kyoto and Saitama Studies
Table 2.
 
Genotype Distribution of ELN Gene SNPs in Control Subjects and in Patients with AMD, tAMD, or PCV in Kyoto and Saitama Studies
Study/Factor rs2301995 AA/AG/GG rs2856728 CC/CT/TT rs868005 CC/CT/TT rs884843 GG/GA/AA rs13239907 GG/GA/AA
Kyoto
    Controls, n (%) 13/99/217 (4/30/66) 25/125/182 (8/38/54) 22/107/203 (7/32/61) 58/167/108 (17/51/32) 133/161/38 (40/49/11)
    AMD, n (%) 50/307/558 (5/34/61) 87/341/479 (10/38/52) 38/324/555 (4/35/61) 170/478/262 (19/52/29) 389/407/118 (43/44/13)
    tAMD, n (%) 28/148/227 (7/37/56) 44/157/198 (11/39/50) 15/136/255 (4/33/63) 80/216/105 (20/54/26) 171/183/48 (43/45/12)
    PCV, n (%) 22/159/331 (4/31/65) 43/184/281 (8/36/56) 23/188/300 (45/37/59) 90/262/157 (18/51/31) 218/224/70 (43/43/14)
Saitama
    Controls, n (%) 5/37/100 (4/26/70) 10/47/82 (7/34/59) 5/28/63 (5/30/65) 17/76/45 (12/55/33) 55/70/15 (39/50/11)
    AMD, n (%) 16/105/234 (5/30/65) 26/118/196 (8/35/57) 11/29/51 (12/32/56) 68/141/125 (20/42/38) 151/160/43 (43/45/12)
    tAMD, n (%) 12/58/134 (6/28/66) 20/65/108 (10/34/56) 9/13/33 (16/24/60) 41/74/71 (22/40/38) 87/90/26 (43/44/13)
    PCV, n (%) 4/47/100 (3/31/66) 6/53/88 (4/36/60) 2/16/18 (6/44/50) 27/67/54 (18/46/36) 64/70/17 (42/47/11)
A statistically significant association was detected between rs2301995 and AMD (P = 0.018; Table 3). When the subtypes of AMD were evaluated, rs2301995 was significantly associated with tAMD (P = 0.0018), with the A allele as a risk, but was not associated with PCV. In both the Kyoto and the Saitama studies, the frequencies of the minor allele of rs2301995 and rs2856728 were higher in tAMD, whereas they were similar in controls and in PCV. The genotype distributions of rs2301995 and rs2856728 were also significantly different between tAMD and PCV (P = 0.00030 and 0.00012). 
Table 3.
 
Association of rs2301995 and rs2856728 to AMD, tAMD, and PCV versus Controls
Table 3.
 
Association of rs2301995 and rs2856728 to AMD, tAMD, and PCV versus Controls
SNP/Factor Allele Genotype Minor Allele
P Value OR (95% CI) P Value Adjusted P *
rs2301995
    AMD 0.041 1.22 (1.01–1.48) 0.044 0.018 A
    tAMD 0.0028 1.38 (1.12–1.71) 0.0036 0.0018
    PCV 0.47 1.12 (0.73–1.72) 0.48 0.33
rs2856728
    AMD 0.77 1.05 (0.76–1.45) 0.78 0.28 C
    tAMD 0.37 1.18 (0.83–1.68) 0.40 0.089
    PCV 0.57 0.89 (0.61–1.32) 0.57 0.89
rs868005
    AMD 0.86 0.98 (0.81–1.19) 0.86 0.58 C
    tAMD 0.72 1.15 (0.89–1.47) 0.72 0.67
    PCV 0.55 0.99 (0.79–1.25) 0.55 0.50
rs884843
    AMD 0.23 0.91 (0.78–1.08) 0.22 0.42 G
    tAMD 0.098 0.86 (0.73–1.03) 0.094 0.11
    PCV 0.59 0.95 (0.81–1.173) 0.59 0.88
rs13239907
    AMD 0.72 1.03 (0.88–1.20) 0.72 0.60 G
    tAMD 0.66 1.04 (0.87–1.24) 0.66 0.51
    PCV 0.84 1.01 (0.85–1.21) 0.84 0.98
Similarly to Kondo et al., 20 we performed a haplotype analysis (Haploview) using three SNPs: rs868005, rs884843, and rs2301995. The estimated frequencies are shown in Table 4. A significant difference was noted for the T–G–A in an analysis between controls and tAMD (P = 0.0055) and also in an analysis between tAMD and PCV (P = 0.014). 
Table 4.
 
Haplotype Distribution of ELN Gene between Controls and tAMD, Controls and PCV, and tAMD and PCV
Table 4.
 
Haplotype Distribution of ELN Gene between Controls and tAMD, Controls and PCV, and tAMD and PCV
Haplotype Haplotype Frequency P Value*
Controls tAMD PCV Controls vs. tAMD Controls vs. PCV tAMD vs. PCV
TAG 0.58 0.53 0.56 0.045 0.56 0.12
CGG 0.23 0.21 0.22 0.45 0.84 0.50
TGA 0.18 0.23 0.19 0.0055 0.54 0.014
TGG 0.015 0.017 0.018 0.70 0.62 0.92
Discussion
In the study reported herein, we showed that the ELN polymorphism is associated significantly with AMD, and subtype analysis revealed that ELN is a susceptibility gene for tAMD but not for PCV. Our findings are consistent with those of a previous report by Kondo et al. 20 in that ELN is a susceptibility gene for AMD. However, in that report they showed that the ELN polymorphism is associated with PCV, but not with tAMD. Furthermore, they reported that MAFs of rs2301995 and rs2856728 were higher in PCV, whereas they were similar in controls and in tAMD (Table 5). This is opposite to our findings—that the MAFs of rs2301995 and rs2856728 are higher in tAMD and are similar in controls and in PCV. The genotype distributions of rs2301995 and rs2856728 had a similar trend between the Kyoto and Saitama studies. Although further investigation is needed, the consistent trend in genotype distribution in the Kyoto study and in the Saitama study suggests that ELN is a susceptibility gene for tAMD, but not for PCV. 
Table 5.
 
Comparison of rs2301995 and rs2856728 Minor Allele Frequency
Table 5.
 
Comparison of rs2301995 and rs2856728 Minor Allele Frequency
Factor rs2301995 A Allele Frequency rs2856728 C Allele Frequency
Kyoto Saitama Pooled Kondo et al. 20 Kyoto Saitama Pooled Kondo et al. 20
Controls 0.19 0.17 0.18 0.15 0.26 0.24 0.26 0.24
tAMD 0.25* 0.20 0.24* 0.14 0.31 0.27 0.30* 0.18
PCV 0.20 0.18 0.19 0.26† 0.27 0.22 0.26 0.32†
In Caucasians, Lima et al. 21 evaluated the ELN rs2301995 polymorphism in 66 patients with PCV and in 368 unaffected controls, and showed that it was not associated with PCV. Ennis et al. 22 also evaluated three ELN SNPs, rs868005, rs2071307, and rs11770302, in 479 AMD patients and in 479 controls, and showed that ELN is not associated with AMD in Caucasians. According to the report by Lima et al., 21 the MAFs of the rs2301995 SNP in Caucasians were 6.3% in PCV, 5.4% in AMD, and 7.1% in controls, which are relatively lower than the MAFs in Japanese, which are reported to be 14–17%. Evaluating associations of SNPs whose MAFs are low tends to lead to false-negative results. For example, many East Asian studies reported that CFH Y402H SNP, the most significantly associated gene locus for Caucasian AMD, is not associated with AMD. 26 31 More recent studies, performed with a larger cohort or meta-analysis, however, revealed an association of the Y402H SNP to AMD, tAMD, and PCV in East Asians. 19,32 Further study with a larger cohort might be required to investigate the association of ELN rs2301995 SNP in Caucasians. 
In the present study, haplotype analysis also supports the theory that ELN is associated with tAMD, not with PCV, in Japanese. The A–G–T haplotype was more prevalent in tAMD than that in controls and, furthermore, was significantly more prevalent in tAMD than that in PCV. However, Kondo and associates 20 reported that the A–G–T haplotype was more prevalent in PCV than that in controls or tAMD. The difference between our findings and the previous report by Kondo et al. 20 might stem from selection bias or diagnosis difference among facilities. Furthermore, the association detected in our study and the previous study might be false-positive findings. In the present study, only one SNP of rs2301995 showed a significant association. When Bonferroni correction was applied, the P values of rs2301995 between control and tAMD become 0.042 in allele analysis and 0.027 in genotype analysis. The P value of the A–G–T haplotype between control and tAMD becomes 0.017. Further evaluation by other facilities would be indispensable. 
The differences between tAMD and PCV in prognosis, reaction to treatments, and prevalence according to ethnicity suggest to us that the pathogenesis of tAMD and PCV is different, at least in part. Histopathologic studies have evaluated the pathologic features of PCV, and whereas some studies showed that the choroidal neovascularization of PCV is the same as that of tAMD, others showed that PCV consists of abnormalities of the inner choroidal vessels, and these differences have not led to a definitive understanding of the pathogenesis of these diseases. 24,25,33 38 Nakashizuka et al. 38 reported a lack of VEGF positivity in the vascular endothelial cells of PCV. In contrast, two other reports have shown the expression of VEGF in PCV 35,36 to be the same as that in CNV membranes secondary to tAMD. 39 Considered together with the relatively poor effects that anti-VEGF treatment have on PCV, VEGF gene polymorphism seems to be an attractive candidate in which to explore the difference between tAMD and PCV. However, evaluation of a previous report indicates no difference in VEGF gene polymorphism between tAMD and PCV. 11 Although the association difference of ELN to tAMD and PCV needs to be carefully judged from both the present study and previous studies, histopathologic studies of elastin expression in tAMD and PCV might reveal a difference in the pathogenesis between PCV and tAMD. 
In summary, our findings indicate an association of the elastin gene variant with tAMD, but not with PCV, in Japanese subjects, but, since our findings are opposite those of previous studies, further investigation is warranted, and a genetic study may well deepen our understanding of the pathogenesis of tAMD and PCV. 
Footnotes
 Supported in part by the Japan Society for the Promotion of Science (Tokyo, Japan) Grants-in-Aid for Scientific Research 21249084 and 200791294, and the Japan National Society for the Prevention of Blindness, Tokyo, Japan.
Footnotes
 Disclosure: K. Yamashiro, None; K. Mori, None; I. Nakata, None; T. Tsuchihashi, None; K. Horie-Inoue, None; H. Nakanishi, None; A. Tsujikawa, None; M. Saito, None; T. Iida, None; R. Yamada, None; F. Matsuda, None; S. Inoue, None; T. Awata, None; S. Yoneya, None; N. Yoshimura, None
References
Uyama M Wada M Nagai Y . Polypoidal choroidal vasculopathy: natural history. Am J Ophthalmol. 2002;133:639–648. [CrossRef] [PubMed]
Ciardella AP Donsoff IM Huang SJ Costa DL Yannuzzi LA . Polypoidal choroidal vasculopathy. Surv Ophthalmol. 2004;49:25–37. [CrossRef] [PubMed]
Honda S Kurimoto Y Kagotani Y Yamamoto H Takagi H Uenishi M . Photodynamic therapy for typical age-related macular degeneration and polypoidal choroidal vasculopathy: a 30-month multicenter study in Hyogo, Japan. Jpn J Ophthalmol. 2009;53:593–597. [CrossRef] [PubMed]
Honda S Imai H Yamashiro K . Comparative assessment of photodynamic therapy for typical age-related macular degeneration and polypoidal choroidal vasculopathy: a multicenter study in Hyogo prefecture, Japan. Ophthalmologica. 2009;223:333–338. [CrossRef] [PubMed]
Yamashiro K Tsujikawa A Nishida A Kurimoto Y . Determinants of patient satisfaction with photodynamic therapy for neovascular age-related macular degeneration or polypoidal choroidal vasculopathy. Jpn J Ophthalmol. 2007;51:368–374. [CrossRef] [PubMed]
Gomi F Sawa M Sakaguchi H . Efficacy of intravitreal bevacizumab for polypoidal choroidal vasculopathy. Br J Ophthalmol. 2008;92:70–73. [CrossRef] [PubMed]
Hikichi T Ohtsuka H Higuchi M . Improvement of angiographic findings of polypoidal choroidal vasculopathy after intravitreal injection of ranibizumab monthly for 3 months. Am J Ophthalmol. 2011;150:674–682. [CrossRef]
Kokame GT Yeung L Lai JC . Continuous anti-VEGF treatment with ranibizumab for polypoidal choroidal vasculopathy: 6-month results. Br J Ophthalmol. 2011;94:297–301. [CrossRef]
Tsujikawa A Ooto S Yamashiro K Tamura H Otani A Yoshimura N . Treatment of polypoidal choroidal vasculopathy by intravitreal injection of bevacizumab. Jpn J Ophthalmol. 2011;54:310–319. [CrossRef]
Maruko I Iida T Saito M Nagayama D Saito K . Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol. 2007;144:15–22. [CrossRef] [PubMed]
Mori K Horie-Inoue K Gehlbach PL . Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population. Ophthalmology. 2010;117:928–938. [CrossRef] [PubMed]
Klein RJ Zeiss C Chew EY . Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–389. [CrossRef] [PubMed]
Haines JL Hauser MA Schmidt S . Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419–421. [CrossRef] [PubMed]
Edwards AO Ritter R3rd Abel KJ Manning A Panhuysen C Farrer LA . Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421–424. [CrossRef] [PubMed]
Hageman GS Anderson DH Johnson LV . A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227–7232. [CrossRef] [PubMed]
Rivera A Fisher SA Fritsche LG . Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet. 2005;14:3227–3236. [CrossRef] [PubMed]
Dewan A Liu M Hartman S . HTRA1 promoter polymorphism in wet age-related macular degeneration. Science. 2006;314:989–992. [CrossRef] [PubMed]
Yang Z Camp NJ Sun H . A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992–993. [CrossRef] [PubMed]
Hayashi H Yamashiro K Gotoh N . CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci. 2010;51:5914–5919. [CrossRef] [PubMed]
Kondo N Honda S Ishibashi K Tsukahara Y Negi A . Elastin gene polymorphisms in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci. 2008;49:1101–1105. [CrossRef] [PubMed]
Lima LH Merriam JE Freund KB . Elastin rs2301995 polymorphism is not associated with polypoidal choroidal vasculopathy in Caucasians. Ophthalmic Genet. 2011;32:80–82. [CrossRef] [PubMed]
Ennis S Jomary C Mullins R . Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet. 2008;372:1828–1834. [CrossRef] [PubMed]
Yu HG Liu X Kiss S . Increased choroidal neovascularization following laser induction in mice lacking lysyl oxidase-like 1. Invest Ophthalmol Vis Sci. 2008;49:2599–2605. [CrossRef] [PubMed]
Kuroiwa S Tateiwa H Hisatomi T Ishibashi T Yoshimura N . Pathological features of surgically excised polypoidal choroidal vasculopathy membranes. Clin Exp Ophthalmol. 2004;32:297–302. [CrossRef]
Okubo A Sameshima M Uemura A Kanda S Ohba N . Clinicopathological correlation of polypoidal choroidal vasculopathy revealed by ultrastructural study. Br J Ophthalmol. 2002;86:1093–1098. [CrossRef] [PubMed]
Gotoh N Yamada R Hiratani H . No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese. Hum Genet. 2006;120:139–143. [CrossRef] [PubMed]
Uka J Tamura H Kobayashi T . No association of complement factor H gene polymorphism and age-related macular degeneration in the Japanese population. Retina. 2006;26:985–987. [CrossRef] [PubMed]
Fuse N Miyazawa A Mengkegale M . Polymorphisms in complement factor H and hemicentin-1 genes in a Japanese population with dry-type age-related macular degeneration. Am J Ophthalmol. 2006;142:1074–1076. [CrossRef] [PubMed]
Mori K Gehlbach PL Kabasawa S . Coding and noncoding variants in the CFH gene and cigarette smoking influence the risk of age-related macular degeneration in a Japanese population. Invest Ophthalmol Vis Sci. 2007;48:5315–5319. [CrossRef] [PubMed]
Kim NR Kang JH Kwon OW Lee SJ Oh JH Chin HS . Association between complement factor H gene polymorphisms and neovascular age-related macular degeneration in Koreans. Invest Ophthalmol Vis Sci. 2008;49:2071–2076. [CrossRef] [PubMed]
Chen LJ Liu DT Tam PO . Association of complement factor H polymorphisms with exudative age-related macular degeneration. Mol Vis. 2006;12:1536–1542. [PubMed]
Kondo N Bessho H Honda S Negi A . Complement factor H Y402H variant and risk of age-related macular degeneration in Asians: a systematic review and meta-analysis. Ophthalmology. 2011;118:339–344. [CrossRef] [PubMed]
Lafaut BA Aisenbrey S Van den Broecke C Bartz-Schmidt KU Heimann K . Polypoidal choroidal vasculopathy pattern in age-related macular degeneration: a clinicopathologic correlation. Retina. 2000;20:650–654. [PubMed]
Rosa RHJr Davis JL Eifrig CW . Clinicopathologic reports, case reports, and small case series: clinicopathologic correlation of idiopathic polypoidal choroidal vasculopathy. Arch Ophthalmol. 2002;120:502–508. [CrossRef] [PubMed]
Terasaki H Miyake Y Suzuki T Nakamura M Nagasaka T . Polypoidal choroidal vasculopathy treated with macular translocation: clinical pathological correlation. Br J Ophthalmol. 2002;86:321–327. [CrossRef] [PubMed]
Matsuoka M Ogata N Otsuji T Nishimura T Takahashi K Matsumura M . Expression of pigment epithelium derived factor and vascular endothelial growth factor in choroidal neovascular membranes and polypoidal choroidal vasculopathy. Br J Ophthalmol. 2004;88:809–815. [CrossRef] [PubMed]
Nakajima M Yuzawa M Shimada H Mori R . Correlation between indocyanine green angiographic findings and histopathology of polypoidal choroidal vasculopathy. Jpn J Ophthalmol. 2004;48:249–255. [CrossRef] [PubMed]
Nakashizuka H Mitsumata M Okisaka S . Clinicopathologic findings in polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci. 2008;49:4729–4737. [CrossRef] [PubMed]
Kvanta A Algvere PV Berglin L Seregard S . Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 1996;37:1929–1934. [PubMed]
Table 1.
 
Characteristics of Study Population
Table 1.
 
Characteristics of Study Population
Factor Kyoto Saitama
Controls tAMD PCV Controls tAMD PCV
Number 336 408 518 142 216 154
Mean age ± SD, y 74.2 ± 8.4* 77.7 ± 8.4* 75.1 ± 8.5* 68.4 ± 9.8† 72.7 ± 8.7† 71.8 ± 7.8†
Sex, male/female 142/194‡ 293/115‡ 381/137‡ 74/68‡ 158/58‡ 122/32‡
Table 2.
 
Genotype Distribution of ELN Gene SNPs in Control Subjects and in Patients with AMD, tAMD, or PCV in Kyoto and Saitama Studies
Table 2.
 
Genotype Distribution of ELN Gene SNPs in Control Subjects and in Patients with AMD, tAMD, or PCV in Kyoto and Saitama Studies
Study/Factor rs2301995 AA/AG/GG rs2856728 CC/CT/TT rs868005 CC/CT/TT rs884843 GG/GA/AA rs13239907 GG/GA/AA
Kyoto
    Controls, n (%) 13/99/217 (4/30/66) 25/125/182 (8/38/54) 22/107/203 (7/32/61) 58/167/108 (17/51/32) 133/161/38 (40/49/11)
    AMD, n (%) 50/307/558 (5/34/61) 87/341/479 (10/38/52) 38/324/555 (4/35/61) 170/478/262 (19/52/29) 389/407/118 (43/44/13)
    tAMD, n (%) 28/148/227 (7/37/56) 44/157/198 (11/39/50) 15/136/255 (4/33/63) 80/216/105 (20/54/26) 171/183/48 (43/45/12)
    PCV, n (%) 22/159/331 (4/31/65) 43/184/281 (8/36/56) 23/188/300 (45/37/59) 90/262/157 (18/51/31) 218/224/70 (43/43/14)
Saitama
    Controls, n (%) 5/37/100 (4/26/70) 10/47/82 (7/34/59) 5/28/63 (5/30/65) 17/76/45 (12/55/33) 55/70/15 (39/50/11)
    AMD, n (%) 16/105/234 (5/30/65) 26/118/196 (8/35/57) 11/29/51 (12/32/56) 68/141/125 (20/42/38) 151/160/43 (43/45/12)
    tAMD, n (%) 12/58/134 (6/28/66) 20/65/108 (10/34/56) 9/13/33 (16/24/60) 41/74/71 (22/40/38) 87/90/26 (43/44/13)
    PCV, n (%) 4/47/100 (3/31/66) 6/53/88 (4/36/60) 2/16/18 (6/44/50) 27/67/54 (18/46/36) 64/70/17 (42/47/11)
Table 3.
 
Association of rs2301995 and rs2856728 to AMD, tAMD, and PCV versus Controls
Table 3.
 
Association of rs2301995 and rs2856728 to AMD, tAMD, and PCV versus Controls
SNP/Factor Allele Genotype Minor Allele
P Value OR (95% CI) P Value Adjusted P *
rs2301995
    AMD 0.041 1.22 (1.01–1.48) 0.044 0.018 A
    tAMD 0.0028 1.38 (1.12–1.71) 0.0036 0.0018
    PCV 0.47 1.12 (0.73–1.72) 0.48 0.33
rs2856728
    AMD 0.77 1.05 (0.76–1.45) 0.78 0.28 C
    tAMD 0.37 1.18 (0.83–1.68) 0.40 0.089
    PCV 0.57 0.89 (0.61–1.32) 0.57 0.89
rs868005
    AMD 0.86 0.98 (0.81–1.19) 0.86 0.58 C
    tAMD 0.72 1.15 (0.89–1.47) 0.72 0.67
    PCV 0.55 0.99 (0.79–1.25) 0.55 0.50
rs884843
    AMD 0.23 0.91 (0.78–1.08) 0.22 0.42 G
    tAMD 0.098 0.86 (0.73–1.03) 0.094 0.11
    PCV 0.59 0.95 (0.81–1.173) 0.59 0.88
rs13239907
    AMD 0.72 1.03 (0.88–1.20) 0.72 0.60 G
    tAMD 0.66 1.04 (0.87–1.24) 0.66 0.51
    PCV 0.84 1.01 (0.85–1.21) 0.84 0.98
Table 4.
 
Haplotype Distribution of ELN Gene between Controls and tAMD, Controls and PCV, and tAMD and PCV
Table 4.
 
Haplotype Distribution of ELN Gene between Controls and tAMD, Controls and PCV, and tAMD and PCV
Haplotype Haplotype Frequency P Value*
Controls tAMD PCV Controls vs. tAMD Controls vs. PCV tAMD vs. PCV
TAG 0.58 0.53 0.56 0.045 0.56 0.12
CGG 0.23 0.21 0.22 0.45 0.84 0.50
TGA 0.18 0.23 0.19 0.0055 0.54 0.014
TGG 0.015 0.017 0.018 0.70 0.62 0.92
Table 5.
 
Comparison of rs2301995 and rs2856728 Minor Allele Frequency
Table 5.
 
Comparison of rs2301995 and rs2856728 Minor Allele Frequency
Factor rs2301995 A Allele Frequency rs2856728 C Allele Frequency
Kyoto Saitama Pooled Kondo et al. 20 Kyoto Saitama Pooled Kondo et al. 20
Controls 0.19 0.17 0.18 0.15 0.26 0.24 0.26 0.24
tAMD 0.25* 0.20 0.24* 0.14 0.31 0.27 0.30* 0.18
PCV 0.20 0.18 0.19 0.26† 0.27 0.22 0.26 0.32†
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×