¡¡¡¡ANGIOTENSIN CONVERTING ENZYME GENE

¡¡¡¡Angiotensin converting enzyme(ACE) is a zinc metallopeptidase widely distributed on the surface of endothelial and epithelial cells. It has been known that ACE contributes to the regulation of systemic hemodynamics by converting angiotensin I to angiotensin ¢ò, a potent vasoconstrictor that increases intraglomerular pressure and glomerular filtration. Therefore, it has been suggested that an elevation of ACE plasma concentration may be associated with the microvascular complication of diabetes[49]. The gene encoding ACE is located on the long arm of chromosome 17 (17q23), which is 21 kilo bases (kb) long and comprises 26 exons and 25 introns[50]. In 1990, Rigat  et al first found a polymorphism involving the presence (insertion, I) or absence (deletion, D) of a 287ª²bp sequence of DNA in intron 16 of this gene[51]. Later studies showed that the involvement of the I/D polymorphism was not limited to ACE levels in plasma, and was also detected in tissue ACE levels[52,53].

¡¡¡¡Because of the central role of ACE in the reninª²angiotensin system, numerous studies have addressed the role of the I/D polymorphism in microvascular disorders, particularly in diabetes[54,55]. Preliminary studies suggested that ACE levels are elevated in type II diabetes, chiefly in patients with retinopathy[56]. Matsumoto et al[57] reported a significant relationship between the presence of the D allele polymorphism in the ACE gene and advanced diabetic retinopathy in Japanese subjects with type 2 diabetes. However, several studies examined the ACE insertion/deletion(I/D) polymorphism and found no association with DR[58ª²65]. The reason for these conflicting results is unclear. There are some possible reasons: one is the racial difference of the subject populations; another is the difference in the method of selecting diabetics for the studies. So additional studies are required to confirm the association between ACE gene and retinopathy in different ethnic populations.

¡¡¡¡VASCULAR ENDOTHELIAL GROWTH FACTOR GENE

¡¡¡¡Vascular endothelial growth factor (VEGF) is an endothelial cellª²specific mitogen in vitro and an angiogenic inducer in a variety of models in vivo. It has been implicated in the pathogenesis of diabetic retinopathy and suggested that the upª²regulation of the VEGE gene is mainly due to hypoxia caused by the obstruction of small arteries in the retina[66]. Elevations of VEGF levels in the aqueous and vitreous humor of human eyes with proliferative retinopathy secondary to diabetes and other conditions have been described. These studies demonstrated a temporal correlation between VEGF elevations and active proliferative retinopathy[67].

¡¡¡¡The human VEGF gene is organized in eight exons separated by seven introns and is localized to chromosome 6p21.3. The coding region spans approximately 14kb[68]. Previous studies have shown that VEGF expression is increased in patients with diabetic microvascular complications and found that polymorphisms in the promoter region of VEGF are associated with susceptibility to diabetic microvascular complications[69]. Awata et al[70] found that Cª²634G polymorphism in the 5¬ðª²untranslated region of the vascular endothelial growth factor gene was significantly associated with DR. Later they confirmed the important role of Cª²634G in susceptibility to retinopathy and analyzed the Cª²2578A and Gª²1154A polymorphisms of VEGF, but neither was associated with the development of DR[71].

¡¡¡¡PIGMENT EPITHELIUMª²DERIVED FACTOR GENE

¡¡¡¡Pigment epitheliumª²derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. It was first purified from conditioned medium of human retinal pigment epithelial cells as a factor with potent neuronal differentiating activity[72]. Recently, PEDF has been shown to be a highly effective inhibitor of angiogenesis in cell culture and animal models. PEDF inhibits the growth and migration of cultured endothelial cells, and it potently suppresses ischemiaª²induced retinal neovascularization[73ª²75]. PEDF levels in aqueous or vitreous humour decreased in patients with diabetes, especially those with proliferative diabetic retinopathy (PDR)[76ª²78]. Furthermore, PEDF knockout mice showed several retinal abnormalities, such as morphological alterations and increased microvessel density[79]. These observations suggest that the loss of PEDF activity in the eye may contribute to the pathogenesis of PDR. A recent study identified four polymorphisms in the PEDF SNPs and found rs12150053 and rs12948385 were significantly associated with diabetic retinopathy. The findings examined that the GA or AA genotype of rs12948385 was a risk factor for DR. Therefore, PEDF is an attractive candidate gene for DR[80,81].

¡¡¡¡THE FUTURE

¡¡¡¡It is clear that the dissection of the genetics of diabetic retinopathy is far from easy. The methodology used so far has had a number of flaws, whereas some clues to the role of genes in retinopathy may have been gleaned and no clinically significant genetic marker has been found. In the future, a combined approach will certainly be required. This involves the use of association studies in large populations followed by analysis within families. The latter will usually involve a transmission disequilibrium test analysis of the frequency of transmission of designated alleles from heterozygous parents to affected offspring. This method has the advantage of requiring fewer pedigrees than affecting sib pair analysis and requires DNA only from both parents and the affected proband.

¡¡¡¡Futhermore, with the development of the human genome project, the genomic sequence data will supply a wealth of information for the identification of mutations in various disease complications such as diabetic retinopathy and offer the greatest hope for identifying the principal genetic components of diabetes complications. There is a growing need for largeª²scale studies on the susceptibility genes for treatment and prevention of diabetic retinopathy.

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