鄭坤坤　綜述　　易湘龍　審校

(新疆醫(yī)科大學第一附屬醫(yī)院眼科， 烏魯木齊　830054)

?

免疫機制及基因多態(tài)性在糖尿病視網(wǎng)膜病變中作用的研究進展

鄭坤坤綜述易湘龍審校

(新疆醫(yī)科大學第一附屬醫(yī)院眼科， 烏魯木齊830054)

糖尿病視網(wǎng)膜病變(diabetic retinopathy,DR)是糖尿病最常見的微血管并發(fā)癥，DR的發(fā)病率和致盲率逐年增加，嚴重影響患者生存質(zhì)量。DR病因復(fù)雜，發(fā)病機制并未完全明確，越來越多的研究表明，DR是一種多因素協(xié)同作用的疾病，DR的免疫機制及基因多態(tài)性機制越來越受到重視。

免疫； 基因多態(tài)性； 糖尿病視網(wǎng)膜病變

糖尿病的全球發(fā)病人數(shù)不斷增加，據(jù)國際糖尿病聯(lián)盟(IDF)統(tǒng)計:2015年全世界已有約4.15億成年人患有糖尿病，每11個成年人中便有1人患有糖尿病[1]。2002年調(diào)查我國糖尿病患病率約3.2%，2010我國成人糖尿病患病率約為9.7%，已經(jīng)成為世界上糖尿病患者最多的國家[2]。Ruta等[3]根據(jù)33個國家的72篇文獻研究發(fā)現(xiàn)在已診斷的2型糖尿病患者中視網(wǎng)膜病變率為10%～61%，中間患病率約27.9%。DR的發(fā)病與糖尿病病程、血糖水平、血壓、血脂等公認的危險因素相關(guān)，但不能完全解釋其發(fā)生發(fā)展，研究發(fā)現(xiàn)免疫學機制及基因多態(tài)性的機制在DR發(fā)病中起重要作用,現(xiàn)將DR的免疫機制和相關(guān)基因多態(tài)性研究進展綜述如下。

1　DR免疫機制的研究現(xiàn)狀

較多證據(jù)表明DR是一種慢性免疫異常性疾病，表現(xiàn)為低度炎癥與炎癥介質(zhì)的參與[4]，是黏附分子、細胞因子、趨化因子、前列腺素等因子和巨噬細胞、中性粒細胞等炎性細胞參與的復(fù)雜的鏈事件[5]；導致視網(wǎng)膜血管滲透性增加、滲出及新生血管形成等病理改變；以下將對胞間黏附分子-1(ICAM)) 、白細胞介素(IL)、腫瘤壞死因子-α(TNF)等免疫因子在DR中的免疫機制進行綜述。

1.1ICAM-1是免疫球蛋白超家族之一，ICAM-1分子主要表達于內(nèi)皮細胞、上皮細胞及淋巴細胞等表面，血管內(nèi)皮細胞表達最強，可介導抗原提呈細胞與T細胞、T細胞與靶細胞黏附及細胞內(nèi)外的信號轉(zhuǎn)導，在免疫和反應(yīng)中起重要作用。ICAM-1在活化內(nèi)皮細胞上表達對介導循環(huán)白細胞黏附到血管壁和跨內(nèi)皮遷移到血管內(nèi)膜中起到重要作用，是局部組織損傷和炎癥反應(yīng)的關(guān)鍵。視網(wǎng)膜表達ICAM-1的增加被認為在白細胞停滯介導的血-視網(wǎng)膜屏障破壞、毛細血管閉塞和糖尿病視網(wǎng)膜病變中起關(guān)鍵作用[6]。DR患者結(jié)膜細胞及糖尿病大鼠血管內(nèi)皮細胞表達ICAM-1均增多[7-8],并且大鼠實驗發(fā)現(xiàn)血管內(nèi)皮細胞缺血時白細胞會黏附及活化，此時ICAM-1可表達上調(diào)[9]；Nicholson等[10]通過對靈長類動物實驗顯示，如果對其玻璃體進行注射血管內(nèi)皮生長因子(VEGF)，靈長類動物會出現(xiàn)類似DR的病理表現(xiàn)，還發(fā)現(xiàn)血清ICAM-1含量有不同程度的上升，而在注射VEGFR的溶解蛋白后,ICAM-1的含量出現(xiàn)明顯下降，可見ICAM-1與VEGF在DR中起協(xié)同作用。在視網(wǎng)膜，VEGF主要表達于穆勒細胞及血管內(nèi)皮細胞，在糖尿病小鼠視網(wǎng)膜穆勒細胞VEGF基因被敲除后，TNF-α、ICAM-1和核轉(zhuǎn)錄因子kappa(NF-κB)的表達明顯降低，白細胞停滯減輕[11]。在人視網(wǎng)膜毛細血管內(nèi)皮細胞受到TNF-β、IL-1、粒細胞-巨噬細胞集落刺激因子(GM-CSF)等刺激因子誘導時ICAM-1表達可顯著提高，在增殖期糖尿病性視網(wǎng)膜病變(PDR)患者血清中ICAM-1的溶解形式-可溶性細胞間黏附分子1(sICAM-1)隨玻璃體IL-6、TNF-α濃度的升高而增高[12]；并且在DR早期VEGF表達上調(diào)也可以促使ICAM-1表達增加，并且促使白細胞在視網(wǎng)膜黏附停滯[13]。Ugurlu等[14]研究認為ICAM-1能夠調(diào)控早期DR的進展。因為白細胞黏附于血管內(nèi)皮細胞是DR免疫反應(yīng)的發(fā)展的關(guān)鍵事件，因此調(diào)控ICAM的表達或用單克隆抗體、白細胞抗體等抑制白細胞的黏附可以為DR治療提供新的可能性。

1.2TNF-αTNF-α是一種由巨噬細胞及激活的B、T淋巴細胞等多種細胞分泌的細胞因子。DR患者有一個免疫-炎癥活動增加的過程，可表現(xiàn)為血清、玻璃體內(nèi)TNF-α水平升高[15]；也有調(diào)查顯示在PDR患者淚液中其水平升高[16]。TNF-α引起DR可能有以下幾種機制:(1) 與多種IL協(xié)同引起血管通透性增加損傷血-視網(wǎng)膜屏障[17]；(2)提高靶細胞對VEGF的反應(yīng)性，并促進VEGF、血小板源性生長因子(PDGF)等生成釋放并協(xié)同促進增殖作用；(3)啟動細胞凋亡效應(yīng)，促進細胞凋亡[18]，從而在PDR的發(fā)病的免疫途徑中起重要作用[19]；(4)轉(zhuǎn)變ICAM-1表達的形式，與ICAM-1協(xié)同增強視網(wǎng)膜局部炎癥反應(yīng)。Adamiec-Mroczek等[20]檢測出增殖期糖尿病視網(wǎng)膜病變患者ICAM-1、TNF-α、IL-6水平明顯增高，顯示DR患者存在免疫系統(tǒng)的亢進，TNF-α含量也隨著疾病進展呈現(xiàn)出明顯上升趨勢。Gustavsson等[21]研究認為，TNF-α可作為PDR患者的一個獨立的血清檢查標志物。Joussen等[22]采用大劑量非甾體類藥物如阿司匹林、美洛昔康非甾體類抗炎藥物，均可減低視網(wǎng)膜TNF-α水平及ICAM-1的表達；此外對另一種非甾體類藥物雙氯芬酸注射液的隨機雙盲臨床試驗表明，對于輕度糖尿病性黃斑水腫，玻璃體腔注射IVD的治療效果優(yōu)于貝伐珠單抗注射(IVB)[23]。白藜蘆醇是一種天然多酚，主要來源于花生和紅葡萄酒，通過減緩心血管系統(tǒng)的氧化應(yīng)激保護心血管[24]；最近的一項關(guān)于2型糖尿病大鼠研究表明，白藜蘆醇抑制NF-κB和TNF-α的活化并減少視網(wǎng)膜細胞凋亡[25]。

1.3IL白細胞介素是一種可經(jīng)淋巴細胞誘導生成并具有復(fù)雜生物學作用的細胞因子，多種白細胞介素參與DR的發(fā)生、發(fā)展， IL-1α、IL-1β、IL-6、TNF-α可直接誘導新生血管生成與間接通過白細胞成或促使內(nèi)皮細胞產(chǎn)生促血管生成介質(zhì)誘導新生血管生[26-27]。Takeuchi等[28]發(fā)現(xiàn)PDR患者玻璃體內(nèi)IL-4、IL-6、IL-17A、IL-21、IL-22及TNF-α的水平明顯高于血清；IL-23主要作用于記憶T淋巴細胞,具有影響免疫反應(yīng)的作用[29]。多種細胞因子可以協(xié)同作用，如IL-1b可以和TNF-α協(xié)同促使視網(wǎng)膜增殖和收縮[30],局部應(yīng)用濃度為0.45%酮咯酸氨丁三醇，可以顯著降低玻璃體IL-8水平而抑制DR的發(fā)病[31]。

1.4 其他與DR病變相關(guān)免疫因素糖尿病視網(wǎng)膜病變的免疫學機制包含多種因素；從基因?qū)用?、細胞因子、細胞及組織器官層面都有免疫異常。有研究認為DR是血管病變和慢性神經(jīng)炎性反應(yīng)性疾病[32]，因此應(yīng)用色素上皮細胞生長因子、促生長素抑制素、神經(jīng)營養(yǎng)因子也可作為DR的替代療法[33]。朱燕妮等[34]研究也發(fā)現(xiàn)DR患者較健康體檢者普遍存在維生素D水平低下，并進一步觀察給予小劑量活性維生素D治療，不僅可改善其免疫及代謝紊亂，同時還可以減輕DR程度，延緩DR的進展，治療過程安全；Yi等[35]研究發(fā)現(xiàn)1,25(OH)2D3可以顯著抑制外周血單個核細胞增殖及釋放TNF-a、IL-6、IL-17A，是DR發(fā)展的保護性因子。ω-3多不飽和脂肪酸(DHA)是目前公認有效的抑制小膠質(zhì)細胞促炎活化免疫調(diào)節(jié)物[36]，是神經(jīng)保護素D1的前體，在視網(wǎng)膜高度富集，能夠保持感光細胞和視網(wǎng)膜色素上皮細胞的存活率[37]。在糖尿病大鼠模型中，局部注射IL-23Rp19抗體可以改善血-視網(wǎng)膜屏障的結(jié)構(gòu)，提供了治療的可能性[38]。在野生型小鼠糖尿病模型中發(fā)現(xiàn)中性粒細胞抑制因子(NIF)通過拮抗的CD11b抑制初期糖尿病性視網(wǎng)膜病變[39]。孟春梅等[40]實驗結(jié)果顯示，DR大鼠視網(wǎng)膜上有大量IgA、IgG和IgM沉積，與對照組形成非常明顯的反差。在趨化因子配體2(CCL2)敲除小鼠中，出現(xiàn)明顯視網(wǎng)膜血管滲漏及單核細胞浸潤[41]。

2　DR相關(guān)基因多態(tài)性的研究現(xiàn)狀

隨著基因?qū)W方法及多聚酶鏈反應(yīng)等技術(shù)的發(fā)展及應(yīng)用，基因多態(tài)性與DR關(guān)系的研究不斷深入，多種基因多態(tài)性已經(jīng)被證實為DR發(fā)生的獨立危險因素，迄今已篩選出了多種DR的候選基因?；蚨鄳B(tài)性與環(huán)境因素相互作用影響著DR，且基因多態(tài)性存在著較大的種族差異；新的治療策略如基因移植等方法正在發(fā)展，繼早期在遺傳性視網(wǎng)膜病變基因治療成功之后，視網(wǎng)膜血管性疾病的基因治療，如DR正在被研究中[42]。

2.1VEGF基因多態(tài)性VEGF基因是DR候選基因研究中被發(fā)現(xiàn)相關(guān)及單核苷酸(SNP)多態(tài)性最多的一個基因。目前已發(fā)現(xiàn)有3O多種單核苷酸多態(tài)性VEGF基因[43],VEGF基因多態(tài)性與DR具有相關(guān)性[44]。近來有研究發(fā)現(xiàn)VEGF基因多態(tài)性對抗VEGF治療產(chǎn)生一定的影響[45]。不同人群中與DR相關(guān)的基因多態(tài)性位點可能不一樣，如rs17697419、rs17697515與英國及澳大利亞白人DR相關(guān)[46]，rs2010963位點與印度人DR相關(guān)[47]；rs6128位點與美國人DR相關(guān)[48]。Churchill等[49]對位于啟動子區(qū)及5′非編碼區(qū)的9個SNPs和內(nèi)含子區(qū)的5個SNP進行研究發(fā)現(xiàn)，-160C/T、-152A/G及-116A/G3個位點(位于啟動子區(qū))及其組成的單倍體與PDR呈強相關(guān)。較多研究表明，不同基因位點多態(tài)性在不同人群中與DR相關(guān)性不盡一致。

2.2維生素D受體基因多態(tài)性維生素D的主要活性形式1,25-(OH)2D3具有免疫調(diào)節(jié)作用，維生素D3通過與維生素D受體(vitamin D receptor，VDR)結(jié)合介導與靶基因特異性的核苷酸序列相互作用[50]。缺乏活性維生素D可以使內(nèi)皮細胞表達的下游促炎細胞因子IL-6表達增加，且與維生素D含量呈反比[51]。較多研究表明，維生素D受體FoI、BsmI、TaqI、ApaI等位基因多態(tài)性與糖尿病視網(wǎng)膜病變密切相關(guān)[52-53]；2015年在漢族人群中一項研究顯示VDR的f基因可能是中國漢族糖尿病患者易于發(fā)生DR 的危險遺傳性標志[54]。VDR基因多態(tài)性存在著較大的種族差異，故在不同人群中不同多態(tài)性位點與DR的相關(guān)性也不盡相同。

2.3醛糖還原酶(AR)基因編碼AR的ALR2基因定位于人類染色體7q35上，醛糖還原酶是限速多元醇途徑的酶，催化由煙酰胺腺嘌呤二核苷磷酸(NADPH)介導的葡萄糖向山梨醇轉(zhuǎn)化，增加AR表達在糖尿病微血管并發(fā)癥中起重要作用[55]。已經(jīng)有許多研究評估多態(tài)性在AKR1B1基因和DR易感性，以(AC)n二核苷酸微衛(wèi)星多態(tài)性和rs759853最常見的研究。 Katakami等[56]研究認為C-106T為日本2型糖尿病視網(wǎng)膜病變患者的易感基因。AR基因的-106CC基因型能增加巴西高加索人2型糖尿病PDR的風險。2010年Abhary等[57]研究發(fā)現(xiàn)AR基因單核苷酸多態(tài)性中rs9640883 與DR有很高的關(guān)聯(lián)性,而且和DR的病程密切相關(guān)。AR抑制劑(ARI)可以有效地抑制多元醇代謝通路中的關(guān)鍵限速酶-AR活性,阻止或延緩DR的發(fā)生。

DR與免疫及遺傳因素關(guān)系密切，深入研究將將有助于探索DR發(fā)病機制，對DR的預(yù)防、診斷及治療有重要意義。

[1]IDF Diabetes Atlas.6th ed.Brussels B. International Diabetes Federation. http://www.idf.org/diabetesatla.

[2]中國2型糖尿病防治指南(2010年版)[J]. 中國糖尿病雜志, 2012,20(1):1-36.

[3]Ruta LM, Magliano DJ, Lemesurier R, et al. Prevalence of diabetic retinopathy in Type 2 diabetes in developing and developed countries[J]. Diabet Med, 2013,30(4):387-398.

[4]Adamis AP. Is diabetic retinopathy an inflammatory disease[J]. Br J Ophthalmol, 2002,86(4):363-365.

[5]Ascaso FJ, Huerva V, Grzybowski A. The role of inflammation in the pathogenesis of macular edema secondary to retinal vascular diseases[J]. Mediators Inflamm, 2014,37(3):432-441.

[6]Joussen AM, Poulaki V, Le ML, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy[J]. FASEB J, 2004,18(12):1450-1452.

[7]Khalfaoui T, Lizard G, Ouertani-Meddeb A. Adhesion molecules (ICAM-1 and VCAM-1) and diabetic retinopathy in type 2 diabetes[J]. J Mol Histol, 2008,39(2):243-249.

[8]Zhu Y, Zhang XL, Zhu BF, et al. Effect of antioxidant N-acetylcysteine on diabetic retinopathy and expression of VEGF and ICAM-1 from retinal blood vessels of diabetic rats[J]. Mol Biol Rep, 2012,39(4):3727-3735.

[9]Bucolo C, Leggio GM, Drago F, et al. Eriodictyol prevents early retinal and plasma abnormalities in streptozotocin-induced diabetic rats[J]. Biochem Pharmacol, 2012,84(1):88-92.

[10]Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF agents for diabetic retinopathy[J]. Graefes Arch Clin Exp Ophthalmol, 2010,248(7):915-930.

[11]Wang J, Xu X, Elliott MH, et al. Muller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage[J]. Diabetes, 2010,59(9):2297-2305.

[12]Adamiec-Mroczek J, Oficjalska-Mlynczak J. Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes--role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy[J]. Graefes Arch Clin Exp Ophthalmol, 2008,246(12):1665-1670.

[13]Joussen AM, Poulaki V, Qin W, et al. Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo[J]. Am J Pathol, 2002,160(2):501-509.

[14]Ugurlu N, Gerceker S, Yulek F, et al. The levels of the circulating cellular adhesion molecules ICAM-1, VCAM-1 and endothelin-1 and the flow-mediated vasodilatation values in patients with type 1 diabetes mellitus with early-stage diabetic retinopathy[J]. Intern Med,2013,52(19):2173-2178.

[15]Gustavsson C, Agardh CD, Agardh E. Profile of intraocular tumour necrosis factor-alpha and interleukin-6 in diabetic subjects with different degrees of diabetic retinopathy[J]. Acta Ophthalmol, 2013,91(5):445-452.

[16]Costagliola C, Romano V, De Tollis M, et al. TNF-alpha levels in tears: a novel biomarker to assess the degree of diabetic retinopathy[J]. Mediators Inflamm, 2013,9(6):245-249.

[17]Aveleira CA, Lin CM, Abcouwer SF, et al. TNF-alpha signals through PKCzeta/NF-kappaB to alter the tight junction complex and increase retinal endothelial cell permeability[J]. Diabetes, 2010,59(11):2872-2882.

[18]Huang H, Gandhi JK, Zhong X, et al. TNFalpha is required for late BRB breakdown in diabetic retinopathy, and its inhibition prevents leukostasis and protects vessels and neurons from apoptosis[J]. Invest Ophthalmol Vis Sci, 2011,52(3):1336-1344.

[19]Fang M, Meng Q, Guo H, et al. Programmed Death 1 (PD-1) is involved in the development of proliferative diabetic retinopathy by mediating activation-induced apoptosis[J]. Mol Vis, 2015,21:901-910.

[20]Adamiec-Mroczek J, Oficjalska-Mlynczak J. Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes--role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy[J]. Graefes Arch Clin Exp Ophthalmol, 2008,246(12):1665-1670.

[21]Gustavsson C, Agardh E, Bengtsson B, et al. TNF-alpha is an independent serum marker for proliferative retinopathy in type 1 diabetic patients[J]. J Diabetes Complications, 2008,22(5):309-316.

[22]Joussen AM, Poulaki V, Mitsiades N, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression[J]. FASEB J, 2002,16(3):438-440.

[23]Soheilian M, Karimi S, Ramezani A, et al. Intravitreal diclofenac versus intravitreal bevacizumab in naive diabetic macular edema: a randomized double-masked clinical trial[J]. Int Ophthalmol, 2015,35(3):421-428.

[24]Kumar A, Kaundal RK, Iyer S, et al. Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy[J]. Life Sci, 2007,80(13):1236-1244.

[25]Ghadiri SF, Arbabi-Aval E, Rezaei KM, et al. Anti-inflammatory properties of resveratrol in the retinas of type 2 diabetic rats[J]. Clin Exp Pharmacol Physiol, 2015,42(1):63-68.

[26]Voronov E, Shouval DS, Krelin Y, et al. IL-1 is required for tumor invasiveness and angiogenesis[J]. Proc Natl Acad Sci U S A, 2003,100(5):2645-2650.

[27]Naldini A, Leali D, Pucci A, et al. Cutting edge: IL-1beta mediates the proangiogenic activity of osteopontin-activated human monocytes[J]. J Immunol, 2006,177(7):4267-4270.

[28]Takeuchi M, Sato T, Tanaka A, et al. Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients[J]. PLoS One, 2015,10(9):137-144.

[29]Kikly K, Liu L, Na S, et al. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation[J]. Curr Opin Immunol, 2006,18(6):670-675.

[30]Demircan N, Safran BG, Soylu M, et al. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy[J]. Eye (Lond), 2006,20(12):1366-1369.

[31]Schoenberger SD, Kim SJ, Shah R, et al. Reduction of interleukin 8 and platelet-derived growth factor levels by topical ketorolac, 0.45%, in patients with diabetic retinopathy[J]. JAMA Ophthalmol, 2014,132(1):32-37.

[32]Yu Y, Chen H, Su SB. Neuroinflammatory responses in diabetic retinopathy[J]. J Neuroinflammation, 2015,12(10):141-148.

[33]Simo R, Hernandez C. Novel approaches for treating diabetic retinopathy based on recent pathogenic evidence[J]. Prog Retin Eye Res, 2015,48:160-180.

[34]朱燕妮, 盧娟, 陳靜, 等. 活性維生素D治療非增殖型糖尿病視網(wǎng)膜病變的療效[J]. 國際眼科雜志, 2013,13(1):104-106.

[35]Yi X, Sun J, Li L, et al. 1,25-Dihydroxyvitamin D3 Deficiency is Involved in the Pathogenesis of Diabetic Retinopathy in the Uygur Population of China[J]. IUBMB Life, 2016,68(6):445-451.

[36]Antonietta AM, Lavinia SM, De Simone R, et al. Docosahexaenoic acid modulates inflammatory and antineurogenic functions of activated microglial cells[J]. J Neurosci Res, 2012,90(3):575-587.

[37]Bazan NG, Calandria JM, Serhan CN. Rescue and repair during photoreceptor cell renewal mediated by docosahexaenoic acid-derived neuroprotectin D1[J]. J Lipid Res, 2010,51(8):2018-2031.

[38]Xu H, Cai M, Zhang X. Effect of the blockade of the IL-23-Th17-IL-17A pathway on streptozotocin-induced diabetic retinopathy in rats[J]. Graefes Arch Clin Exp Ophthalmol, 2015,253(9):1485-1492.

[39]Veenstra AA, Tang J, Kern TS. Antagonism of CD11b with neutrophil inhibitory factor (NIF) inhibits vascular lesions in diabetic retinopathy[J]. PLoS One, 2013,8(10):235-247.

[40]孟春梅, 高樺, 邱明才, 等. 鏈脲佐菌素誘導的糖尿病大鼠視網(wǎng)膜的免疫損傷[J]. 中華內(nèi)分泌代謝雜志, 2006,22(6):588-589.

[41]Rangasamy S, McGuire PG, Franco NC, et al. Chemokine mediated monocyte trafficking into the retina: role of inflammation in alteration of the blood-retinal barrier in diabetic retinopathy[J]. PLoS One, 2014,9(10):1-10.

[42]Thompson DA, Ali RR, Banin E, et al. Advancing therapeutic strategies for inherited retinal degeneration: recommendations from the Monaciano Symposium[J]. Invest Ophthalmol Vis Sci, 2015,56(2):918-931.

[43]Jain L, Vargo CA, Danesi R, et al. The role of vascular endothelial growth factor SNPs as predictive and prognostic markers for major solid tumors[J]. Mol Cancer Ther, 2009,8(9):2496-508.

[44]Nakamura S, Iwasaki N, Funatsu H, et al. Impact of variants in the VEGF gene on progression of proliferative diabetic retinopathy[J]. Graefes Arch Clin Exp Ophthalmol, 2009,247(1):21-26.

[45]El-Shazly SF, El-Bradey MH, Tameesh MK. Vascular endothelial growth factor gene polymorphism prevalence in patients with diabetic macular oedema and its correlation with anti-vascular endothelial growth factor treatment outcomes[J]. Clin Experiment Ophthalmol, 2014,42(4):369-378.

[46]Abhary S, Burdon KP, Gupta A, et al. Common sequence variation in the VEGFA gene predicts risk of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2009,50(12):5552-5558.

[47]Choudhuri S, Chowdhury IH, Das S, et al. Role of NF-kappaB activation and VEGF gene polymorphisms in VEGF up regulation in non-proliferative and proliferative diabetic retinopathy[J]. Mol Cell Biochem, 2015,405(1-2):265-279.

[48]Sobrin L, Green T, Sim X, et al. Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe)[J]. Invest Ophthalmol Vis Sci, 2011,52(10):7593-7602.

[49]Churchill AJ, Carter JG, Ramsden C, et al. VEGF polymorphisms are associated with severity of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2008,49(8):3611-3616.

[50]朱釗, 韓睿. 維生素D及其受體基因與糖尿病視網(wǎng)膜病變的關(guān)系[J]. 中華糖尿病雜志, 2011,3(6):493-496.

[51]Jablonski KL, Chonchol M, Pierce GL, et al. 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults[J]. Hypertension, 2011,57(1):63-69.

[52]Zhang H, Wang J, Yi B, et al. BsmI polymorphisms in vitamin D receptor gene are associated with diabetic nephropathy in type 2 diabetes in the Han Chinese population[J]. Gene, 2012,495(2):183-188.

[53]Wang G, Zhang Q, Xu N, et al. Associations between two polymorphisms (FokI and BsmI) of vitamin D receptor gene and type 1 diabetes mellitus in Asian population: a meta-analysis[J]. PLoS One, 2014,9(3):1-21.

[54]侯麗君, 黃東輝, 韓靜靜. 維生素D受體基因FokI多態(tài)性與糖尿病視網(wǎng)膜病變的相關(guān)性研究[J]. 泰山醫(yī)學院學報, 2015,(5):490-493.

[55]Nishimura C, Saito T, Ito T, et al. High levels of erythrocyte aldose reductase and diabetic retinopathy in NIDDM patients[J]. Diabetologia, 1994,37(3):328-330.

[56]Katakami N, Kaneto H, Takahara M, et al. Aldose reductase C-106T gene polymorphism is associated with diabetic retinopathy in Japanese patients with type 2 diabetes[J]. Diabetes Res Clin Pract, 2011,92(3):57-60.

[57]Abhary S, Burdon KP, Laurie KJ, et al. Aldose reductase gene polymorphisms and diabetic retinopathy susceptibility[J]. Diabetes Care, 2010,33(8):1834-1836.

(本文編輯張巧蓮)

國家自然科學基金(81260150，81560161)； 國家教育部高等學校博士學科點專項科研基金新教師類(20126517120004)； 中國博士后科學基金面上資助項目(2014M562485)； 新疆醫(yī)科大學第一附屬醫(yī)院青年科研基金(2012QN08)

鄭坤坤(1990-)，男，在讀碩士，研究方向：眼底病診斷與治療。

易湘龍，男，主任醫(yī)師，副教授，碩士生導師，研究方向：眼底病近視矯正及角膜移植，E-mail: xly1010@sina.com。

R77; R392.12

A

1009-5551(2016)09-1098-05

10.3969/j.issn.1009-5551.2016.09.005

2016-03-16]