|Molecular Vision 2005;
Received 20 October 2004 | Accepted 16 June 2005 | Published 23 June 2005
Association between glaucoma and gene polymorphism of endothelin type A receptor
Tomoyo Funayama,1 Yuichiro Ohtake,1 Itaru Kimura,1
Hidenao Ideta,2 Kenji Nakamoto,3 Noriko Yasuda,3 Takeo
Fukuchi,4 Takuro Fujimaki,5 Akira Murakami,5 Ryo
Asaoka,6 Yoshihiro Hotta,6 Takashi Kanamoto,7 Hidenobu
Tanihara,8 Koichi Miyaki,9
Departments of 1Ophthalmology and 9Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan; 2Ideta Eye Hospital, Kumamoto, Japan; 3Department of Ophthalmology, Tokyo Metropolitan Police Hospital, Tokyo, Japan; 4Department of Ophthalmology, Niigata University School of Medicine, Niigata, Japan; 5Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan; 6Department of Ophthalmology, Hamamatsu University School of Medicine, Hamamatsu, Japan; 7Department of Ophthalmology, Hiroshima University School of Medicine, Hiroshima, Japan; 8Department of Ophthalmology, Kumamoto University School of Medicine, Kumamoto, Japan
Correspondence to: Karin Ishikawa, MD, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Phone: (+81) 3-3353-1211, ext. 62402; FAX: (+81) 3-3359-8302; email: firstname.lastname@example.org
Purpose: Endothelin 1 (ET-1), a potent vasoconstrictor, may affect regulation of intraocular pressure and ocular vessel tone. Thus, ET-1 and its receptors may contribute to development of glaucoma. We investigated whether gene polymorphisms of ET-1 (EDN1) and its receptors ETA (EDNRA) and ETB (EDNRB) were associated with glaucoma phenotypes and clinical features.
Methods: We studied 224 normal Japanese controls and 426 open angle glaucoma (OAG) patients including 176 with primary open angle glaucoma (POAG) and 250 with normal tension glaucoma (NTG). Nine single nucleotide polymorphisms were detected among the participants using the Invader® assay; four for EDN1 (T-1370G, +138/ex1 del/ins, G8002A, K198N), four for EDNRA (G-231A, H323H, C+70G, C+1222T), and one for EDNRB (L277L). Genotype distributions were compared between normal controls and OAG. Age at diagnosis, untreated maximum intraocular pressure (IOP), and visual field defects at diagnosis were examined for association with polymorphisms.
Results: Of the 9 polymorphisms, genotype distributions showed no significant differences between OAG patients and controls adjusted by age. The GG genotype of EDNRA/C+70G was associated with worse visual field defects in NTG patients (p=0.014; Mann-Whitney U test, and p=0.027; logistic regression analysis).
Conclusions: The polymorphism of EDNRA/C+70G may be related to NTG risk factors.
Glaucoma is the second leading cause of vision loss worldwide. The number of persons with primary glaucoma was estimated at nearly 66.8 million, including 6.7 million with bilateral blindness . Open angle glaucoma (OAG) is a slowly progressive atrophy of the optic nerve characterized by visual field changes corresponding to excavation of the optic disc . OAG, the most common type of glaucoma, is divided into primary open angle glaucoma (POAG), where elevated intraocular pressure (IOP) is above 21 mm Hg, and normal tension glaucoma (NTG), where IOP does not exceed 21 mm Hg. Among Japanese, NTG accounts for 92% of OAG, a higher proportion than in Caucasians . Although an elevated IOP is a major risk factor, the pathophysiology of OAG is not precisely known. OAG is a multifactorial disease that results from interactions between multiple genetic and environmental factors . Both mechanical and vascular mechanisms have been proposed [2,5].
Recent studies have demonstrated that endothelin and its receptors may contribute significantly to development of the optic neuropathy characteristic of glaucoma [6,7]. Endothelin 1 (ET-1), a potent 21-amino acid vasoconstrictive peptide produced by vascular endothelial cells [8,9], is considered the most important vasoconstrictor among three isopeptides identified (the others being endothelin-2 and endothelin-3). Endothelin receptors, type A (ETA) and type B (ETB), mediate the biological effects of ET-1. The potent vasoconstrictor effect of ET-1 is mediated predominantly by ET-1 specific ETA receptors located on vascular smooth muscle cells and, to a lesser extent, by activation of ETB receptors, which are nonselective among endothelins [10-12].
The presence of the ET system is well established in the eye, where ET and its receptors have been found in most tissues [13-17]. Aqueous humor ET levels were reported to be higher in patients with POAG than in normal subjects [18,19], while Källberg et al.  made the same observations in dogs with hypertensive glaucoma compared with healthy dogs.
Although two studies reported significantly higher plasma ET-1 levels in patients with NTG than in normal control subjects [21,22], Tezel et al.  found no significant difference in plasma ET levels between POAG patients and controls. Kaiser et al.  reported a tendency toward higher plasma ET-1 levels in NTG patients than in POAG patients, although the differences were not statistically significant. They also noted an abnormality in ET-1 production in response to postural changes in NTG patients. In addition, several reports have suggested that glaucomatous nerve fiber damage was affected by vasospasm , systemic vascular endothelial cell dysfunction , and microvascular dysfunction  mediated by ET-1. Thus, ET-1 has been suggested to participate in regulation of IOP and ocular vessel tone, but is also suspected to take part in the pathogenesis of glaucoma.
Population based association studies using polymorphic candidate genes are one approach to identifying genes conferring increased susceptibility to glaucoma. However, the impact of endothelin related genetic polymorphisms on glaucoma is incompletely determined. One previous association study in Australian Caucasians has reported a possible involvement of the ET-1 gene in glaucoma, finding no alterations in the promoter region of the ET-1 gene . In the present study, we investigated whether gene polymorphisms of ET-1 (EDN1), and the receptors ETA (EDNRA) and ETB (EDNRB) were associated with OAG phenotypes and clinical features in a Japanese population.
A total of 650 Japanese subjects (224 normal controls, 176 POAG patients, and 250 NTG patients), recruited from seven Japanese medical institutions, were examined. Blood samples were analyzed at Keio University. All subjects were unrelated. The mean age (±standard deviation) at diagnosis of OAG was 57.2±12.8 years. OAG subjects were divided into POAG patients and NTG patients, aged 58.8±12.2 and 56.1±13.2 years at diagnosis, respectively (Table 1). The mean age at the time of examination was 70.0±11.2 years in controls. We purposely selected older control subjects to reduce the likelihood that a subset of controls would later develop glaucoma.
The procedures used in this human research conformed to the tenets of the Declaration of Helsinki. Written informed consent was obtained after the nature and possible consequences of the study were explained. Where applicable, the research was approved by the Keio Institutional Human Experimentation Committee.
Ophthalmic examinations included slit-lamp biomicroscopy, optic disc examination, IOP measurement by Goldmann applanation tonometry, and gonioscopy. Visual fields were assessed with the Humphrey automated perimetry (program 30-2) or Goldmann perimetry. The severity of the visual field defects was scored from 1 to 5 [28,29]. The data obtained by the two types of perimetry were combined using a five point scale: (1) no alterations, (2) early defects, (3) moderate defects, (4) severe defects, and (5) light perception only or no light perception. This severity scale followed Kozaki's classification [30,31], which has been used most widely in Japan so far, based on Goldmann perimetry or by the classification established for the Humphrey Field Analyzer .
Among the patients with OAG, POAG was diagnosed upon fulfillment of all of the following criteria; maximum IOP was above 21 mm Hg, open angles on gonioscopy, typical glaucomatous disc cupping associated with visual field changes, and absence of other ocular, rhinologic, neurological, or systemic disorders potentially causing optic nerve damage. We excluded patients with elevated IOP secondary to defined causes (e.g., trauma, uveitis, steroid administrtion, or exfoliative, pigmentary, or neovascular glaucoma). POAG patients with MYOC or OPTN mutations and juvenile OAG patients were also excluded. Among the patients with OAG, NTG was diagnosed by the same criteria as POAG except that IOP did not exceed 21 mm Hg at all times, including the three baseline measurements and during the diurnal test (IOP every 3 h from 6 AM to 24 PM), when the peak IOP with or without medication after diagnosis was consistently below 22 mm Hg throughout the follow-up period. Normal control subjects had IOP less than 20 mm Hg, no glaucomatous disc changes, and no family history of glaucoma.
DNA extraction and genotyping of the polymorphisms
Genomic DNA was isolated from peripheral blood lymphocytes by standard methods. Nine single nucleotide polymorphisms (SNPs) were detected among all participants; four for EDN1 (T-1370G, +138/ex1 del/ins, G8002A, K198N), four for EDNRA (G-231A, H323H, C+70G, C+1222T), and one for EDNRB (L277L). These polymorphisms are listed at GeneCanvas. We genotyped these SNPs using the Invader® assay (Third Wave Technologies, Inc., Madison, WI), which was recently developed for high throughput genotyping of SNPs . The oligonucleotide sequences of primary probes and Invader® probes used in this study are listed in Table 2.
Comparisons of genotype distributions in normal controls with those in OAG patients were performed by χ2 analysis. Age adjustments were also performed using logistic regression analysis. Associations of clinical characteristics (age at diagnosis, untreated maximum of IOP, and visual field score at diagnosis) with genotypes were assessed by the Mann-Whitney U test. Multivariate analyses were also performed with a logistic regression model to confirm the association between these clinical characters and the genotypes. Statistical analyses were carried out with SPSS for Windows (version 12.0; SPSS Inc., Chicago, IL). A value of p<0.05 was considered to be significant.
Table 3 shows genotype and allele frequencies obtained in this study. The distributions in control and OAG were consistent with the Hardy-Weinberg equilibrium. For the EDN1/+138/ex1 del/ins polymorphism, the frequencies of the del/del and del/ins+ins/ins genotypes, respectively, were 74.2% and 25.8% in OAG patients (p=0.016), compared with 65.2% and 34.8% in control subjects. For the EDN1/K198N polymorphism, 53.2% of OAG patients were found to have the KK genotype, which tended to be higher than the 43.8% in control subjects (p=0.022). For the EDNRA/C+1222T polymorphism, the frequency of the CT+TT genotype in OAG patients tended to be higher than in control subjects (p=0.036). However, when adjusted by age, these case-control studies did not reveal significant differences between OAG patients and controls. Adjusted p values are shown in Table 3. Polymorphism of EDN1/G8002A in the intron 4 region was highly coincident with EDN1/K198N (data not shown).
Characteristics of patients were examined for a dominant model and a recessive model for each polymorphism, and data with significant differences are shown in Table 4. In all OAG patients and in POAG patients, no characteristic showed a significant difference between genotype groups. In NTG patients, however, we found significantly poorer visual field scores at diagnosis in the GG group for EDNRA/C+70G than the CC+CG group (3.0±0.7 compared to 2.7±0.7, p=0.014; Mann-Whitney U test). Because these three characteristics (age at diagnosis, untreated maximum IOP, and visual field defects at diagnosis) may be linked, the relationships between genotypes were investigated by logistic regression analysis. It still revealed significantly poorer visual field scores in the GG group than the CC+CG group (p=0.027). Other polymorphisms in NTG patients showed no significant differences in characteristics between genotype groups.
Considerable evidence has been collected implicating vascular insufficiency as the cause of glaucomatous nerve fiber damage [24-26,34]. IOP is well recognized to be the only one among multiple factors responsible for optic nerve damage in glaucoma. Endothelium derived NO and ET-1 are potent vascular tone modulators important in regulation of local blood flow in the eye [7,35-39].
Furthermore, according to recent studies, ET-1 influences not only blood flow but also morphological and physiological changes relevant to glaucoma. In a rabbit model, optic nerve head ischemia induced by ET-1 resulted in optic disc excavation, diffuse loss of axons, and demyelination affecting the prelaminar portion of the optic nerve without a change in the IOP [40,41]. ET-1 also decreased the anterograde axonal transport in the rat optic nerve , caused loss of retinal ganglion cells and their axons in rats , and reduced neuronal metabolic activity in the visual cortex of rhesus monkeys . ET-1 induced proliferation in astrocytes cultured from the human optic nerve head by activating ETA and ETB receptors . Astrogliosis is a common major pathologic feature shared by many neuropathies, including glaucoma. ET-1 may also affect aqueous humor dynamics in a complex and sometimes self-opposing manner [46-49].
ETA receptors, the main ET-1 receptor binding sites, are present in the iris, ciliary muscle, ciliary processes, and retina [13,15]. Polak et al.  examined the regulation of human retinal blood flow by ET-1, and they concluded that BQ-123, the specific ETA receptor antagonist, antagonizes the effects of exogenously administered ET-1 on retinal blood flow in healthy subjects. This indicates that the retinal vasoconstrictor effect of ET-1 is mainly mediated via the ETA receptor. In this study, the genotype distributions adjusted by age showed no significant differences between glaucoma patients and controls. On the other hand, the GG genotype of EDNRA/C+70G was associated with more severe visual field defects in NTG patients. This polymorphism did not affect the characteristics of the patients except in NTG patients.
However, the mechanisms by which this polymorphism affects function remain to be determined. Indeed, this polymorphism might be nonfunctional in itself but may be closely linked to a presently uncharacterized functional mutation modifying the expression of the gene. Another possibility might be that the polymorphism is in linkage disequilibrium with another locus, with the causal variant being a small distance away in adjacent regulatory regions or in a nearby gene.
If ET-1 or its receptors are indeed involved in susceptibility to glaucoma, anti-ET-1 therapies are of major interest. Because ET-1 may participate in vascular dysfunction such as vasoconstriction or abnormal autoregulation in glaucoma, an ET-1 blocker or ET-1 receptor antagonist might be of some benefit in glaucoma patients, especially those NTG patients whose glaucoma etiology appears to be vascular insufficiency. For example, isopropyl unoprostone (Rescula®), already used to lower IOP in some glaucoma patients, has been reported to have anti-ET-1 effects in animals and in healthy human subjects [50-52].
In conclusion, our results suggest that the polymorphism of EDNRA/C+70G may be related to NTG risk factors. Glaucoma is caused by actions of many genes, each having a small additive effect, interacting with effects of the environment. Actions of ET-1 and its receptors could be among contributing influences. However, given insufficient present knowledge of the functional mechanisms involving this polymorphism, such findings cannot explain the pathogenesis of glaucoma at this time. Further studies are necessary to assess the functional impact of these polymorphisms on gene expression or structure.
This study was supported by Research on Eye and Ear Sciences from Ministry of Health, Labour and Welfare of Japan.
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