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

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Fig. 1. The ApoE gene organization.

Table 1

ApoE Genotype and Diseases

the most frequent form, has cysteine at 112 and arginine at 158. ApoE2 contains cysteine and ApoE4 arginine at both positions (4). ApoE4 preferentially binds VLDLs, whereas ApoE2 and ApoE3 preferentially bind HDLs. ApoE3 and ApoE4 bind to lowdensity lipoprotein (LDL) receptor with high affinity, but ApoE2 is defective to LDL receptor binding (5). These three isoforms are in dynamic equilibrium and with similar maximum binding capacities. But their selective and differential binding affinities to lipoproteins and receptors lead to important differences in biological functions.

As a major structural and functional component of lipoproteins, ApoE contributes to lipid metabolism and balances in tissue cells throughout the body, including the central nervous system (CNS) (6). Many sporadic or familial forms of dyslipidemia are attributed to ApoE, such as association of type III hyperlipoproteinemia with ApoE2 and type V hyperlipoproteinia with ApoE4. ApoE affects the metabolism of amyloid precursor protein (APP) and is involved in formation of amyloid bodies (7). Pathogeneses of cardiovascular diseases and Alzheimer’s disease (AD) are attributed to ApoE isoforms (3,8). The disease spectrum is wide, extending from type 2 diabetes, multiple sclerosis, impaired cognitive function to ocular disorders, principally the two potentially blinding conditions of age-related macular degeneration (AMD) and primary open-angle glaucoma (POAG) (see Table 1).

CLINICAL PRESENTATIONS OF PRIMARY OPEN-ANGLE GLAUCOMA

Onset of POAG is typical after age 40. It is frequently bilateral but could be asymmetric in severity (9). In its early to moderate stages, POAG is largely an asymptomatic disease. Because the processes leading to retinal ganglion cell loss are gradually progressive over many years. The associated retinal ganglion cell loss and functional deficits, such as mid-peripheral visual field loss, are also slowly progressive and not easily noticed by the patient. Intraocular pressure (IOP) in POAG can sometimes reach levels comparable to those seen in acute forms of glaucoma (10). The increase in IOP has, however, slowly progressed over many years, and so ocular tissues have time to adapt to the high pressure and do not become acutely inflamed and ischemic as in acute glaucoma. Inflammation and ischemia cause most of the symptoms and signs of acute glaucoma, such as ocular pain, ciliary flush, and sluggish pupil (11). The corneal endothelium has time to adapt to the slowly rising IOP in POAG, and so corneal edema does not usually develop, and the majority of patients do not complain of blurring of vision or seeing halo around highlights.

The main functional deficit suffered by early to moderate POAG patients is visual field loss, which may take the form of an arcuate loss, a nasal step, a temporal wedge, or progressive loss in the Bjerrum’s area. Central visual acuity is usually well maintained in these patients, and so visual acuity tests alone often cannot detect the disease. POAG patients are often incidentally diagnosed when they consult ophthalmologists for unrelated eye symptoms or disease (9).

In the advanced stages of the disease, visual field loss may be so extensive that the patient’s activities of daily living become affected. Patients may complain of stumbling over pavements or other objects on the ground. They may have greater difficulty maneuvering stairs and complain of not noticing people or vehicles approaching from

the sides (12). In the advanced stage, only a small island of central vision may be left, and this is often described as “tunnel vision.” The remaining small central visual field could be acutely lost if the processes of retinal ganglion cell loss, such as high IOP or other non-IOP-dependent mechanisms, are not controlled (10). Untreated glaucoma may take an average of 14.4 years to progress from early to end stage at IOP of 21–25 mmHg, 6.5 years at 25–30 mmHg, and 2.9 years at more than 30 mmHg (13).

RISK FACTORS AND PROGNOSTIC FACTORS FOR PRIMARY OPEN-ANGLE GLAUCOMA

Glaucoma can be considered as a collection of eye diseases in which the final common pathological pathway is retinal nerve fiber loss. Even in POAG alone, various mechanisms may be jointly contributing to such optic neuropathy. The relative importance of these mechanisms varies from patient to patient and indeed possibly also from eye to eye. These pathogenic mechanisms may include the following.

Intraocular Pressure

The association of raised IOP with glaucomatous optic nerve fiber loss is well documented, and reduction of IOP in glaucoma patients slows down the loss. Despite the identification of other factors contributing to optic nerve fiber loss in recent years, IOP remains the most important risk factor for glaucomatous progression. IOP can be accurately quantified. It is also the risk factor that can be most readily modified with available medications. Reduction of IOP remains the primary aim of all currently available glaucoma treatments whether medical or surgical.

It has long been known that the increase in IOP is due to an increase in the resistance to aqueous outflow (14). The trabecular meshwork is one important site that may increase the resistance to outflow. Histopathological changes in the trabecular meshwork of glaucoma patients, which may also represent an accelerated aging process, have been well described (15–17). Increase in aqueous outflow resistance may be a result of collapse of Schlemm’s canal (18,19) or altered composition of aqueous (20,21). Both mechanical and vascular mechanisms are likely involved in optic nerve fiber loss because of increased IOP, which may interfere with retrograde axoplasmic flow of essential neurotrophic factors (22,23). Lack of neurotrophic factors may induce programmed cell death, that is, apoptosis, in the retinal ganglion cells (24,25). Increased IOP may also cause optic nerve fiber loss through distortion of the lamina cribrosa architecture (26,27). Alternatively, raised IOP may exert its effects on retinal ganglion cells through alterations of the microvascular circulation in the anterior optic nerve (28).

Circulatory Factors

The mere existence of normal-tension glaucoma teaches us that factors other than IOP must be contributing to glaucomatous optic nerve fiber loss. Changes in the microcirculation or defective autoregulation of blood flow of the optic nerve head may be among these factors (28,29). Nocturnal systemic hypotension may also play a role (30). Nevertheless, reduction of IOP can effectively slow down glaucomatous optic nerve fiber loss even in normal-tension glaucoma patients (31).

Genetic Factors

Family history shows that genetic factors play a role in POAG (32). The genetics of POAG are complex, with links to at least 20 genetic loci (33,34). Mutations in genes located in GLC1A, GLC1E, and GLC1G have been identified in POAG families. Myocilin (MYOC) at GLC1A is mutated in both juvenile and mature-onset POAG patients (35–37), whereas optineurin (OPTN) at GLC1E is mainly mutated in normal-tension POAG patients (38,39). WD repeat-domain 36 (WDR36) at GLC1G, the recently identified causative gene for POAG, was found in approximately 5% familial and sporadic cases of POAG (40). For these three known POAG genes, MYOC is established as directly glaucoma causative. The role of OPTN is unclear and evidence is inconsistent (41–43). The impact of WDR36 on the wider POAG population is still to be determined. However, mutations in these three genes account for only a small fraction of POAG cases, indicating that additional loci or genes are involved in the development of POAG. Polymorphisms in the ApoE gene have been shown to associate with POAG. It is discussed later in this chapter.

Other Risk Factors and Prognostic Factors

Apart from IOP, a host of other risk factors for the development of POAG have been identified, mainly through population-based prevalence studies. In addition to IOP, black race (44,45) and disc hemorrhage (46) have also been identified as poor prognostic factors for POAG. Diabetes mellitus especially in old age aggravates glaucoma (47). Earlier studies had found cigarette smoking to be a risk factor for POAG (48,49). But such association was not found in later studies (50–52). It is interesting to note that an association between myopic refraction with prevalence of open-angle glaucoma was shown in a Japanese study (53).

THE APOE GENE

The ApoE gene is located on chromosome 19q13.2 in a cluster with ApoC1 and ApoC2 (see Fig. 1). It contains a 5´-regulatory sequence of about 1.4 kb, 3 introns, and 4 exons spanning 3.6 kilobases and encoding a single-polypeptide chain of 299 amino acids (54,55). The ApoE mRNA sequence is composed of 1163 nucleotides (56). ApoE is highly polymorphic with the three major isoforms ApoE2, ApoE3, and ApoE4 encoded by alleles 2, 3, and 4, respectively, in codominant inheritance of two cSNPs at 3937 and 4075 in exon 4 (1,4,57). There are accordingly six genotypes: 2/ 2,2/ 3, 2/ 4, 3/ 3, 3/ 4, and 4/ 4. The most common allele, that is, the wildtype, is 3. A study on the 5.5-kb sequence spanning the ApoE gene from a multi-ethnic sample revealed 22 SNP, showing an overall nucleotide heterozygosity of 0.0007 and a rate of variation occurrence at 1 per 1400 bp (58). Therefore, there are substructures within the 2, 3, and 4 alleles whose structural and biomedical effects are to be characterized.

The ApoE promoter region has been determined for about 1.4 kb upstream of the transcription initiation site with the proximal promoter region approximately from nucleotides –1000 to +400 (59,60). But about 18 kb downstream, there is a 319-bp hepatocyte-specific control region that modulates ApoE and ApoCI expression in the

Table 2

Studies on ApoE Polymorphisms in Open-Angle Glaucoma

liver (61,62). In the promoter, the TATA box is located at –27 to –33. A binding site has been found for transcription factor AP-1 at –602 from the initiation point. Two sites were detected for AP-2 at –120 and –60 (63). There are at least three enhancer elements, URE1 (–246 to –81), URE2 (–366 to –246), and IRE1 (+44 to +262). A positive element for transcription located from –161 to –141 within URE1 is capable of acting as an independent enhancer (64). A tissue-specific element URE3 was located at –101 to –89, a GC box transcriptional control element at –59 to –45, plus other cisacting elements, transcription regulatory elements, and estrogen-responsive elements mostly within the region –360 to –80. The ApoE regulatory sequence is polymorphic (65). Three single-nucleotide biallelic polymorphisms have been well studied in their effects on ApoE expressions and association with disease risk: –219T/G, –427C/T, and –491A/T (66,67). Independent of 4 status, –491AA carriers have significantly higher plasma ApoE levels than carriers of –491AT and –491TT (68). Association of the ApoE genotype with open angle glaucoma has been studied in different ethnic groups (see Table 2).

PATHOPHYSIOLOGICAL ROLES OF APOE

By virtue of its structural adherence to lipoproteins and binding affinities to various lipoprotein receptors among various cells of the body, ApoE plays key roles in metabolism, transport, and distribution of lipids, including cholesterol. Consequently, alterations in functions and structures of ApoE and differential expressions of its major isoforms affect the cardiovascular and neurological systems. But its effects have been shown to be far-reaching, associating with development and clinical features of a wide spectrum of diseases or disorders (see Table 1). Association studies of ApoE with coronary vascular disease (CVD), AD, and AMD have been extensively reported.

Coronary Vascular Disease

The three common ApoE isoforms have differential binding capacities, ApoE2 and ApoE3 preferentially to HDLs and ApoE4 to VLDLs (4). But ApoE3 and ApoE4 bind to LDL receptor with high affinity, whereas ApoE2 binds with defective affinity

(3). ApoE2 is associated with type III hyperlipoproteinemia (HLPIII), which is the major familial form of ApoE deficiency. In HLPIII, impaired clearance of chylomicron and VLDL remnants because of defective ApoE leads to elevated plasma cholesterol and triglyceride. Most HLPIII patients are homozygous for 2, but a 10-bp deletion and an Arg136Cys mutation have also been found (69). ApoE genotype, accordingly, has direct effects on diseases related to lipid metabolism. The 2 and 4 alleles alone are associated with hyperlipidaemia but are influenced by ethnicity, gender, and lifestyle (8,70). 2 carriers have increased risk of atherothrombosis, cardioembiolism, and intracerebral hemorrhage and 4 for atherothrombosis, intracerebral hemorrhage, and subarachnoid hemorrhage (71). The 4 allele, mediated by increased plasma cholesterol and triglyceride and decreased HDL-cholesterol, is a prominent risk factor for cardiovascular diseases (3,72). It is associated with hypertriglyceridemia in NIDDM patients with hyperlipidemia types IIb and V, whereas the 2 allele is associated with types III and IV (73). 4 appeared to reduce the risk of nephropathy in NIDDM,

whereas the 2 allele increased the risk (74). Results of different reports, however, are not necessarily consistent. A meta-analysis of 31 studies involving 5931 patients and 17,965 controls showed that 4 is associated with ischemic stroke in smaller studies but not in larger studies with more than 200 study cases (75). Sample size and study design should be stringently controlled for results to be trustworthy. Attention should also be paid to regulatory or structural variations in ApoE other than the 2, 3, and4 alleles (58). The non-coding SNPs, A560 and T830, have recently been shown to have positive predictive values for dyslipidemia (76).

Alzheimer’s Disease

The 4 allele is a strong genetic determinant of late-onset AD, with a dosage effect and interactive influence by other genetic and environmental factors (77,78). While the4 allele alone is not a necessary or sufficient condition to cause AD, 4 homozygosity may be sufficient to cause AD by the age of 80 (78). 2, on the contrary, may confer some protective effect against AD. ApoE4 plays many roles leading to the pathogenesis of AD. It increases amyloid plagues and neurofibrillary tangles. But the ApoE4 protein promotes amyloid protein a?ggregation less effectively than does ApoE3, indicating that ApoE4 induces AD by hindering neuron repair or by accelerating amyloid plaque formation. In one study involving 417 patients and 1030 controls, the odds ratio of AD possessing 2 was 0.5, against a risk effect of 4 with odds ratio 2.7 (78). The2 protective effect was more marked in another study, with an odds ratio of 0.08 (79). Histologically, 2 may lead to lower neurofibrillary tangle and senile plague density and thus protects against AD (80). We have shown that although the 4 allele in Chinese is present at a lower frequency than Caucasians, it also increases risk of late-onset AD and is associated with -amyloid load (81,82).

Two polymorphisms in the 5´-regulatory region, –491A/T (69) and 186G/T (83), were recently found to associate with increased risk for AD, suggesting a role of altered ApoE transcription in the pathogenesis of AD. The –491, –427, and –219 polymorphisms in the proximal promoter all confer susceptibility to AD likely through altering the ApoE expressions in specific cell types. The –491AA genotype may be an independent risk factor for AD (84). –219G→ T decreases ApoE expression and increases risk of heart disease (85).

Age-Related Macular Degeneration

In the retina, ApoE is produced by Müller cells, and increased immunoreactivity is found in AMD, in drusen, and as basal laminar deposits in maculae (86). The 4 allelic frequency was lower (p < 0.0009) in patients with exudative AMD than in control subjects (86). Among 88 AMD patients aged 55 or above, 4 exerted a decreased risk (odds ratio 0.43) while 2 an increased risk (OR = 1.5) when compared with 901 control subjects (87). In a study of 98 Chinese AMD patients, we have shown a small trend toward reduced ApoE 4 allele frequency compared to 133 control subjects (88). This is consistent with a protective effect of 4 in other studies (81,89). One report on Caucasians gave no effects of any ApoE alleles to development of AMD (90). In a large cohort of 632 AMD patients and 206 controls, decreased risk of 4 was established, but effect of 2, whether posing risk or protection, remained equivocal