Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

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genetic markers in genetic mapping studies. In addition, understanding the associated polymorphisms may provide an increased understanding of the molecular mechanism of a disease. In this chapter, we review some useful genetic polymorphic markers for glaucoma from serial genetic polymorphism screenings.

We enrolled OAG patients from the department of ophthalmology at the China Medical University Hospital from May to July 2003. All patients in this study received complete ophthalmic examinations, which included intraocular pressure (IOP), visual acuity, automated perimetry, gonioscopy, optic disc examination, and retinal examination. Patients with ocular diseases other than OAG were excluded from our study. The control population was obtained from a group of patients undergoing routine examination, and the patients were examined by the same ophthalmologist. Volunteers suspected of having glaucoma or any other ocular disease were excluded from the study. Patients included in the OAG arm of the study were required to have at least one of the following criteria:

1.Visual field criteria: At least two abnormal visual field tests by Humphreyautomated perimetry, as defined by computer-based objective criteria. (The presence of one or more absolute defects in the 30° central visual field, attributed to glaucomatous visual field loss.)

2.Optic disc criteria (by fundus photographs): Either a horizontal or vertical cup- to-disc ratio of 0.6 or more, with narrowest remaining neuroretinal rim 20% or less of disc diameter, attributed to glaucomatous damage.

3.No secondary mechanism for the glaucomatous damage nor any other ocular cause for the disc and field changes.

This study was carried out with the approval of the Human Study Committee of the China Medical University Hospital. Informed consent was obtained from all patients who participated in the study. The genomic DNA was prepared from peripheral blood, using a Genomaker reagent kit (Blossom, Taiwan). Polymerase chain reaction (PCR) was used to identify the genotypes of all of the related genes. The polymorphisms were analyzed by primers for each oligonucleotide to create the sequences recognized by restriction endonucleases, and the reactions were followed by PCR. The products of PCR were loaded into agarose gel containing ethidium bromide for electrophoresis, and each allele was identified according to its size. For statistical analysis, the allelic frequency distributions of the polymorphism in the control and OAG patient groups were compared using the chi-square test. When the assumption of the chi-square test was violated (i.e. when one cell had an expected count of <1 or >20% of the cells had an expected count of <5), the Fisher’s exact test was used. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined for disease susceptibility of specific alleles in the candidate polymorphisms. Results were considered statistically significant when the probability of findings occurring by chance was less than 5% (p < 0.05).

Sixty-six patients with OAG and 100 healthy controls were enrolled in this study. The OAG patients ranged in age from 20 to 70 years (mean, 55 years), and 33 were females. The control group ranged in age from 52 to 71 years (mean, 50 years), and 52 were females. No subjects in either study arms were related. All subjects were followed-up from 2 to 8 years (mean 5 years). Ten of the glaucoma patients had received trabeculectomy, with two requiring a repeat procedure at a different site. Fifty

OAG patients were controlled on an average of 1.3 topical anti-glaucomatous drugs and nine did not require glaucoma medication following trabeculectomy.

The following are observations form our studies and the literature.

GLAUCOMA AND APOPTOSIS

Although the glaucomas represent a complex and only a partially understood group of diseases, with mechanical and vascular mechanisms being the most commonly accepted hypotheses, the ultimate death of retina ganglion cells (RGCs) represents the final common pathway in glaucomatous vision loss (8,9). Several studies have demonstrated that RGCs die during the glaucomatous process by a form of cell death known as apoptosis (10,11). One of the primary regulatory steps of apoptosis is the activation of the tumor-suppressor protein, p53, which is one of the major guardians of the genome and can either arrest the cell cycle in response to DNA damage or direct the damaged cell to an apoptotic pathway. Cell cycle arrest can be achieved either by a non-transcriptional route or more commonly by the transcriptional activation of p53 (12,13). p53 functions as a transcription factor that can up-regulate the expression of the pro-apoptotic gene, bax, and down-regulate the expression of the anti-apoptotic gene, bcl-2 (12,13). Changes in the concentrations of these gene products can stimulate apoptotic events, including changes in the mitochondria, and ultimately lead to the activation of cysteine proteases (caspases), which digest the dying cell from within.

Among polymorphisms of p53 genes, we found that p53 codon 72 genetic polymorphism is closely related to OAG. Many structural features of p53 (residues 61–94) have been well resolved except residue 72, which has been recognized as an arginine (Arg) to prolinine (Pro) polymorphism. Some findings indicate that the p53 codon 72 polymorphism has been associated with many tumor formations in Chinese patients (14,15). The single base change from CGC to CCC caused the alteration of amino acid residue 72 from Arg to Pro (16). In our study, there is a significant difference in the distribution of the polymorphism between the control subjects and the OAG patients (17). The Pro form of p53 gene codon 72 appears to be a significant risk factor in the development of OAG (17). The hypothesis is that the Arg form of p53 in residue 72 may be responsible for the less potent effects when the cell is destined to replicate. The Pro form of p53 gene codon 72 induces instability of RGCs, rendering them unable to regenerate; that is, the Pro form allele fails to protect RGC from apoptosis.

In most glaucoma patients, progressive changes in the visual field and optic nerve are related to increased IOP. However, many people with IOP above the normal range suffer no clinical damage during their life, whereas in other cases, IOP in the normal range is too high for proper function of the optic nerve (i.e. normal-tension glaucoma) (18). It appears, therefore, that IOP is simply one causative risk factor but not the only factor in the mechanism of RGCs loss in glaucoma patients (19). It may be a combination of an IOP level and the influence of a genetic mutation that leads to RGC apoptosis (11). We suspect that the Pro form of p53 gene codon 72 induces instability of RGCs and fails to protect them from apoptosis.