【摘要】 糖尿病性视网膜病变是糖尿病的眼部慢性并发症，为成人致盲的主要原因。糖尿病患者长期处于高血糖状态将导致糖尿病性视网膜病变的形成。一些研究表明合理控制血糖是预防糖尿病病变的重要措施。然而，越来越多的家族聚集性和不同种族发病率的研究显示基因对于糖尿病性视网膜病变的发病有重要作用。一些糖尿病患者尽管血糖控制良好仍发展成糖尿病性视网膜病变，而另有一些患者尽管血糖控制不良却没有形成糖尿病性视网膜病变。这表明很多基因与糖尿病性视网膜病变的易感性有关，这些基因用于编码醛糖还原酶，氧化氮合酶，晚期糖化终产物受体，血管紧张素转换酶，血管内皮生长因子和色素上皮衍生因子。易感性基因的研究将有助于形成新的治疗策略。本文对糖尿病性视网膜病变形成和发展中相关遗传基因进行综述。
【关键词】 糖尿病性视网膜病变 易感性基因
INTRODUCTION
Diabetes mellitus is a worldwide medical problem and is a significant cause of mortality. Micro and macrovascular complications are highly prevalent among the diabetes patients[1]. Diabetic retinopathy (DR), one of the most important complications in both Type 1 and Type 2 diabetes, has become the leading cause of vision loss and blindness in workingage adults in both developed and developing countries. Visual loss results mainly from central macular edema, and less frequently from proliferative diabetic retinopathy (PDR). The development of these pathological changes is strongly related to hyperglycemia[2]. Although the Diabetes Control and Complications Trial showed that a tight control of hyperglycemia can reduce the incidence of retinopathy, it is clear that hyperglycemia alone does not explain the development of this complication. It may be absent in some patients with poor glycemia control even over a long period time, while others may develop retinopathy in a relatively short period despite good glycemia control, possibly as a result of hereditary factors. The strongest evidence for a genetic predisposition towards DR derives from twin, family and transracial studies. Early reports from identical twins study showed that the stage of retinopathy has been found to be similar, demonstrating the importance of inherited factors in the etiology of diabetes retinopathy[3].
Over the past several years, some studies were under way evaluating genetic links to diabetic retinopathy. The genes that influence these conditions may be the suitable candidate genes. The search for candidate genes that predict risk of DR is important for a number of reasons. First, it will define a group of diabetic subjects who are predisposed to retinopathy at the time of diabetes diagnosis. This group could then be offered careful followup and possible early therapeutic intervention. Second, insights into the pathogenesis of the condition may be developed by establishing the identity and function of the candidate genes, ultimately facilitating new therapeutic approaches[4]. In order to identify these genes, there is a range of approaches from limited evaluations of single genetic polymorphism in small casecontrol studies to systematic evaluations of the human genome, using genome scans and linkage analysis in a large collection of families. Broadly speaking, there are two molecular strategies, candidate gene analysis and whole genome scans, and two analytical approaches, association studies and linkage studies. Association studies compare the frequency of specific alleles of a genetic marker between different populations, conventionally casecontrol populations. Linkage studies evaluate the inheritance of a genetic locus in families. Molecular genetic analysis combining association and linkage is the most powerful approach for assessing genetic contributions to diabetes complications[5].
The following genetic loci have been the focus of investigation regarding a possible role in the development of DR. This article reviewed the current status of these genes and their association with DR.
ALDOSE REDUCTASE GENE
Although prolonged exposure to hyperglycemia is the primary factor associated with the development of most diabetes complications, it is also evident that genetic factors play an important role in determining the risk for the microvascular complications. The polyol pathway as one of the physiological mechanisms linking hyperglycemia has been considered important in the development of diabetes retinopathy[6].
Aldose reductase is the first and ratelimiting enzyme in the polyol pathway[7]. It converts glucose to sorbitol, and sorbitol dehydrogenase converts sorbitol to fructose[8,9]. Aldose reductase is widely expressed in tissues, including retinal capillaries and pericytes. An osmoregulatory role for this enzyme is supported by the rapid and specific increases in its activity and gene expression, which occur upon exposure to hypertonic media. Increased glucose flux through this enzymatic pathway with intracellular sorbitol accumulation leads to several abnormalities in cellular metabolism, which may contribute to the death of retinal pericytes and hence damage to endothelial cells, an early event in the development of diabetic retinopathy[10,11]. Several studies have pointed out that a high level of aldose reductase in the erythrocyte of both Type 1 and Type 2 diabetic patients is associated with the presence of retinopathy[12,13].
Human aldose reductase gene, the gene encoding aldose reductase has been localized at the chromosome 7q35 and consists of 10 exons extending over 18 kilobases of DNA. There is growing evidence supporting that aldose reductase gene has been strongly associated with diabetic microvascular disease. Variants in the aldose reductase gene may cause increased level or activity of the enzyme, and thus contribute to diabetic retinopathy[14,15]. Polymorphism of this gene have been suggested to exert an effect on the natural history of DR. This finding was supported by an early study that showed an (AC)n dinucleotide repeating polymorphic marker at 5 end of the aldose reductase gene was first described and Z2 was associated with early onset of DR in Type 1 diabetes[16], which was similar to several current studies suggesting that in type 2 diabetics having similar glycemic control, the (AC)23 allele is related to a progression rate of retinopathy 8.9 times higher than in diabetics who lack it[17] and the Z2 and C106 alleles are associated with the microvascular complications while the Z+2 and T106 may be protective factors[1820]. Kao et al[21]have identified a single substitution of A for C at 95th nucleotide of intron 8 in 164 adolescents with type 1 diabetes in whom DR was assessed and have reported that the BB genotype was significantly more common in adolescents with early DR than those without retinopathy. The study suggested that polymorphism of the aldose reductase gene was associated with DR. Chromosome 7q35 was considered a candidate genetic locus for susceptibility to DR[21]. Two more studies performed on Asian, European and African populations had shown that the frequency of the C(106)T polymorphism of the aldose reductase gene had a significant association with retinopathy and that type 2 diabetics with the CC genotype were more susceptible to developing retinopathy than those with the CT or TT genotype, giving additional evidence for the CC genotype as genetic marker of retinopathy[2225]. Thus, genotyping of the 106C>T polymorphism in the aldose reductase gene could be useful as a tool in the identification of diabetic patients who are more prone to develop DR, and thereby require a more intensive treatment in order to prevent the progression of DR.
NITRIC OXIDE SYNTHASE GENE
Nitric oxide(NO) plays a pivotal role in the regulation of vascular homeostasis and is produced in endothelial cells by endothelial nitric oxide synthase (eNOS). The intraluminal release of nitric oxide mediates local vasodilatation, antagonizes platelet aggregation and inhibits vascular smooth muscle proliferation[26]. In response to stimuli such as hypoxia and stress, the vascular endothelial cells synthesize nitric oxide from Larginine by a constitutive, calcium/calmodulindependent enzyme known as eNOS[27]. Abnormality in nitric oxide availability plays an important role in the pathophysiology of diabetic vascular disease, which involves impaired endotheliumdependent relaxation. A growing amount of clinical and experimental evidence suggests that the pathogenisis of diabetic retinopathy is associated with a heterogeneous and complex constellation of retinal disorders in the nitric oxide pathway including increased ocular NO levels, aberrant retinal NO utilization, impaired NOmediated vasodilation, oxidative and nitrative stress, dysregulation of NO synthase isoforms, and endothelial NO synthase uncoupling[2830]. Therefore, human eNOS gene, as well as other NOS genes, represents a
plausible candidate gene responsible for DR.
The locus for the eNOS gene is on the long arm of chromosome 7. The gene contains 26 exons spanning approximately 21 kilobases of genomic DNA, encodes a messenger RNA of 4052 nucleotides, and is present as a single copy in the haploid human genome[31]. Three polymorphisms in the eNOS gene have been widely studied: a single nucleotide polymorphism (SNP) in the promoter region(T786C), a SNP in exon 7(Glu298Asp), and a variable number of tandem repeats(VNTR) in intron 4[32,33].
Several studies have shown significant associations between eNOS polymorphism and the development or severity of diabetic retinopathy in patients with type 1 diabetes mellitus(T1DM)[3436], while a few studies have reported no association between eNOS polymorphism and DR in T2DM patients[3739]. A group from Paris reported a strong association between the eNOS4b/a endothelial nitric oxide synthase polymorphism and severe DR[40] and their another finding suggested that T789C and C774T eNOS polymorphism affected the onset pattern of severe DR[41]. Therefore, whether eNOS gene should be considered as a candidate gene in DR or not await a largescale prospective study.
GENE OF RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS
Diabetes mellitus is associated with oxidative and carbonyl stress, microinflammation and eventually autoimmune reaction. Advanced glycation end products are represented by a heterogeneous group of compounds, which are formed from Schiff bases and amadori products when reducing sugars such as glucose react nonenzymatically with amino groups in proteins, lipids, and nucleic acids through a series of reactions. The ability to form crosslinks to and between proteins, and their interactions with a class of binding sites on endothelial cells and monocytes, as well as other cell types lead to tissue damage in diabetic complications[42]. Among several etiopathological mechanisms proposed in diabetic retinopathy, advanced glycation end products (AGEs) formed due to nonenzymatic glycation of proteins is one of the key components causing microvascular complications[43].
AGEs can exert biological activity via specific receptors, among them the best known is receptor for advanced glycation end products (RAGE). RAGE, a 35kDa protein, has been isolated and cloned form the bovine lung and has been classified as a member of the immunoglobulin superfamily, which is expressed on endothelial cells, mononuclear phagocytes and vascular smooth muscle cells[44]. The AGE RAGE interaction are thought to be involved in the development of diabetic complications, including retinopathy. The RAGE gene is located on chromosome 6p21.3 in the major histocompatibility coplex locus in the class Ⅲ region[45]. Genetic polymorphism in the RAGE could influence AGEs processing in tissues or reactions following the AGE binding to RAGE, and thereby accelerates the development and severity of glucosemediated tissue damage. Several RAGE gene polymorphisms have shown association with the pathological states of diabetic complications[46]. Hudson et al[47] screened for polymorphisms in the coding regions of RAGE gene and found seven polymorphisms in exons and two in introns. Meanwhile, four functional amino acid changes were detected: Gly82Ser(exon3), Thr187Pro(exon 6), Gly329Arg(exon 8), and Arg389Gln(exon 10)[47]. Gly82Ser polymorphism is particularly interesting because of relatively high prevalence and the polymorphism results in the creation of an Alu I restriction site (AG/CT). Later study from Asian populations investigated the frequency of Gly82Ser polymorphism in exon 3 of the RAGE gene and its association with DR. Their study suggested that Ser82 allele in the receptor for AGE gene is a lowrisk allele for developing DR[48]. Therefore, polymorphisms resulting in functional amino acid changes in the RAGE gene may influence development of DR by altering the AGERAGE interaction.
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