遵义市汉族居民Eales病人类白细胞抗原基因多态性和结核感染的相关性研究

目的 探讨遵义市汉族Eales病与人类白细胞抗原(HLA)-A/B、HLA-DRB/DQB基因多态性和结核感染的相关性.方法 采用聚合酶链反应序列特异引物法(PCR-SSP)检测Eales病组、肺结核组、正常对照组HLA-A/B、HLA-DRB/DQB共59个等位基因分布频率,计算各组间优势比(OR)及95%可信区间(CI);对Eales病组与肺结核组的HLA-A*02基因分布频率做相关分析.Eales病组为临床确诊的Eales病患者47例;肺结核组为痰结核菌培养确诊肺结核并排除眼部疾病的患者36例;正常对照组为与研究组患者年龄、性别、民族等因素无差异的100名健康人.Easle病组中,资料完整的39例Eales病患者根据病史及纯结核菌素试验(PPD)检查结果分为4组,a组为既往或现在患肺结核患者,12例;b组为无结核感染患者,27例;c组为PPD检查阳性者,27例;d组为PPD阴性者,12例.结果 Eales病组HLA-A*02(OR=9.719,OR 95%CI为4.377～21.580,P=0.000)、HLA-B*07(OR=11.605,OR 95%CI为2.397～56.191,P=0.001)基因分布频率高于正常对照组,差异有统计学意义,HLA-A*11基因分布频率低于正常对照组,差异有统计学意义(OR=0.495,OR 95%CI为0.245～1.000,P=0.048).肺结核组HLA-DRB*16(OR=5.215,P=0.049)、HLA-A*02(OR=18.87,P=0.000)基因分布频率高于正常对照组,差异有统计学意义,HLA-A*24基因分布频率低于正常对照组,差异有统计学意义(OR=5.690,P=0.015).a组与b组,c组与d组比较:HLA-A*02、HLA-A*11、HLA-B*07基因分布频率差异无统计学意义.在Eales病组、肺结核组、正常对照组间,HLA-A*02、HLA-A*24、HLA-B*07、HLA-DRB*16基因总体分布频率比较,差异均有统计学意义,进一步行x2分割法在Eales病组、肺结核组间两两比较,肺结核组HLA-A*24基因分布频率低于Eales病组,差异有统计学意义(x2=7.289,P=0.007),而HLA-A*02基因分布频率无统计学意义(OR=0.515,P=0.202).Eales病组与肺结核组HLA-A*02基因相关性比较,差异无统计学意义(列联系数0.412,P=0.064).结论 Eales病可能存在遗传易感性,HLA-A*02和HLA-B*07可能是遵义市汉族Eales病患者的遗传易感基因,而HLA-A*11可能是保护基因;HLA-DRB*16和HLA-A*02可能是遵义市汉族肺结核病的易感基因,而HLA-A*24可能是保护基因.HLA-A*02可能是遵义市汉族人群中Eales病和肺结核病共同的易感基因.

Abstract：

Objective To analyze the relationship of human leukocyte antigen alleles (HLA-A/B,HLA-DRB/DQB) polymorphism and Eales disease, tuberculosis infection in a Han population in Zunyi city of China. Methods The subjects were analyzed by case-control study, which consisted of three groups including Eales disease group (47 patients), pulmonary tuberculosis group (36 patients) and normal control group (100 healthy people). Thirty-nine patients in Eales disease group who had complete history were divided into 4 subgroups according to the history and tuberculin PPD test. Twelve patients with past or present pulmonary tuberculosis were in group A, 27 patients without pulmonary tuberculosis were in group B, 27 patients with positive PPD test were in group C, and 12 patients with negative PPD test were in group D. Fifty-nine alleles of HLA-A/B and HLA-DRB/DQB were analyzed by polymerase chain reaction with sequence-specific primers (PCR-SSP) in all subjects. Odds ratios between each group (OR) and 95%confidence interval (CI) were calculated; Frequency distribution of HLA-A * 02 gene were analyzed for the group A and the TB group. Results The frequency distribution of HLA-A* 02 (OR=9. 719, OR 95% CI:4. 377-21. 580, P=0. 000) and HLA-B* 07 (OR= 11. 605, OR 95% CI: 2. 397-56. 191, P=0. 001) alleles in Eales disease group were obviously higher than that in normal control group, but frequency distribution of HLA-A * 11 (OR = 0. 495, OR 95% CI: 0. 245-1. 000, P= 0. 048) in Eales disease group was obviously lower than that in normal control group. There was no significant difference in frequency distribution of HLA-A * 02, HLA-A * 11 and HLA-B* 07 alleles between groups A and B, and between groups C and D (P＞0. 05). The distribution frequency of HLA-A * 02, HLA-A * 24, HLA-B * 07 and HLA-DRB * 16alleles among Eales disease group, pulmonary tuberculosis group and control group was statistically different (P＜0. 05). The frequency distribution of HLA-A * 24 alleles in pulmonary tuberculosis group was lower than that in Eales disease group (x2 = 7. 289, P = 0. 007), but the frequency distribution of HLA-A * 02 alleles had no significant difference (OR=0. 515, P=0. 202) between two groups. Conclusions The alleles of HLA-A * 02 and HLA-B * 07 may be genetic predisposing genes of Eales disease, but HLA-A * 11 alleles may be protective gene in population of Han nationality from Zunyi city. The alleles of HLA-DRB * 16 and HLA-A * 02 may be genetic predisposing genes of pulmonay tuberculosis. The alleles of HLA-A * 02 may be a common susceptible gene for Eales disease and pulmonary tuberculosis. HLA-A * 11 and HLA-A * 24 alleles were protective genes of Eales disease and pulmonary tuberculosis respectively.     

Eales病与人类白细胞抗原-DRB、DQB基因位点的关联

目的 分析Eales病与人类白细胞抗原（HLA）DRB和DQB基因位点的相关性，探讨Eales病可能的免疫遗传学机制。 方法 采用聚合酶链反应-序列特异性引物法（PCR-SSP）检测27例北方汉族Eales病患者以及30名正常对照者HLA-DRB、DQB基因位点，用SPSS 12.0统计软件分析两组人群HLA-DRB、DQB1等位基因频率的分布特点。 结果 与正常对照组比较，Eales病患者HLA-DRB1*04等位基因频率明显增高（P=0.047,OR=3.20,OR 95% 可信区间为1.00～10.21）, 两组间其他DRB 和DQB1等位基因频率的分布差异均无显著性(P>0.05)。 结论 中国北方汉族人群中，DRB1*04等位基因与Eales病呈正相关，可能是Eales病的遗传易感基因。Eales病患者可能因其特定的HLA遗传素质而易受致病因子攻击出现免疫功能紊乱，从而促成Eales病的发生与发展。 (中华眼底病杂志, 2006, 22: 90-93)     

HLA与Eales病相关性研究

目的探讨北方汉族HLA-DRB和-DQB1基因位点与Eales病及病情严重性的相关性。方法应用病例-对照相关分析方法,采用PCR-序列特异性引物基因分型技术对北方汉族30名健康个体和21例Eales病患者(均无血缘关系)进行HLA-DRB和-DQB1进行遗传相关分析。结果Eales病患者中DRB1*04的频率为(0.57)显著高于对照组(0.02),χ2=7.46,P<0.01,比数比(OR)为5.33。DRB1*11的频率(0.05)显著低于对照组(0.30),χ2=4.99,P〈0.05,OR为0.17。DRB1*04阳性患者最终平均视力明显低于DRB1*4阴性患者,并且DRB*04阳性患者行玻璃切割手术治疗的频率高于DRB*04阳性患者,但二者没有统计学差异(P>0.05)。结论北方汉族HLA-DRB等位基因与Eales病相关,DRB1*04可能与Eales病易感相关;DRB1*11可能在发病中有保护作用。     

我国汉族Vogt-Koyanagi-Harada综合征患者人类白细胞抗原DQB1等位基因多态性研究

目的探讨人类白细胞抗原（HLA）-DQB1等位基因多态性与沃格特-小柳-原田综合征（VKH）遗传易感相关性及与临床表现的关系。方法应用聚合酶链式反应-序列特异性引物（PCR—SSP）,对我国汉族VKH患者和非VKH正常对照者HLA-DQB1等位基因进行分型,分析HLA-DQB1等位基因与患者临床表现的关系。结果收集我国汉族VKH患者88例,非VKH正常对照者88例。VKH患者中男性41例（46．6％）,女性47例（53．4％）;发病年龄15—67岁,平均36岁。VKH患者HLA—DQB1各等位基因频率：HLA-DQB1＊0401为31．8％,DQB1＊0201为17．6％,DQB1＊0301／＊0304为17．1％,DQB1＊0602为12．5％,DQB1＊0303为6．8％,DQB1＊0302为6．3％,DQB1＊0402为1．7％,DQB1＊0502为1.7％,DQB1＊0601为1．7％,DQB1＊0501为1．1％,DQB1＊050为31．1％,DQB1＊0604为0．6％;DQB1＊0603未检出。VKH患者中HLA—DQB1＊0401（VKH组31．8％与对照组4．5％比较,r=44．00,P=0．000,OR=9．8,95％口为4．51—21．31）和HLA—DQB1＊0303（VKH组6．82％与对照组0．57％比较,〈=9．67,P=0．002,伽=12．81,95％CI为1.65—99．58）等位基因频率高于正常人对照组,差异有统计学意义。而VKH患者HLA—DQB1＊0601（VKH组1.7％与对照组9．7％比较,r=10．39,P=0．001,OR=0．16,95％CI为0．05—0．56）和HLA—DQB1＊0302（VKH组6．3％与对照组19．3％比较,r=13．48,P=0．000,OR=0．28,95％CI为0．14—0．57）等位基因频率显著低于正常人对照组,差异有统计学意义。HLA-DQB1＊0401阴性患者与阳性患者之间的临床表现差异无统计学意义（P〈0．01）。结论（I）HLA—DQB1＊0401和DQB1＊0303是VKH的易感等位基因,而HLA-DQB1＊0601和DQB1＊0302是抗性等位基因。HLA-DQB1＊0401基因与临床表现无明显相关性。（2）PCR-SSP可用于快速检测HLA—DQB1等位基因型别。     

阅读时戴低度凸透镜对小学生近视干预效果评价

目的 评价阅读时戴低度凸透镜对小学生近视的干预效果。 设计 前瞻性队列研究。 研究对象 594例1～5年级的近视高危（双眼裸眼视力≥4.7,－1.0 D≤双眼等效球镜值≤2.0 D）的小学生。阅读时戴低度凸透镜者286例为干预组,平均年龄（7.81±1.48）岁;未戴低度凸透镜者308例为对照组,平均年龄（8.44±1.59）岁。方法 2010年底（基线）和2011年底（终线）分别对594例1～5年级的小学生行屈光度检查。根据终线时的检查结果（取右眼数据）,以近视进展情况（终线右眼等效球镜－基线右眼等效球镜）、近视发病情况作为结局指标,分别采用多重线性回归分析和logistic回归分析评价干预效果,并且按照性别和年级（1～3年级VS 4～5年级）进行分层分析。主要指标 右眼等效球镜度数。结果 干预前后干预组右眼等效球镜变化（-0.35±0.76）D,较对照组（-0.56±0.71）D少（P=0.004）。女生干预组较对照组有效（P=0.003）,男生干预组与对照组无统计学差异（P=0.317）。1～3年级干预组较对照组有效（P<0.001）,而4～5年级干预组与对照组无统计学差异（P=0.678）。终线时,干预组和对照组近视发病率分别为14.3%和29.5%。与对照组相比,干预组近视发病的OR值为0.593（95%CI=0.371~0.946）;按性别分层,男生和女生干预组近视发病的OR值分别为0.704 （95%CI=0.358~1.385）和0.450（95%CI=0.227~0.894）;按年级分层,1～3年级和4～5年级干预组近视发病的OR值分别为0.440（95%CI=0.238~0.813）和1.143（95%CI=0.478~2.731）。结论 阅读时戴低度凸透镜,尤其是女学生和低年级学生,可以减缓近视发展的进程,降低近视发病率,对小学生近视防治起到积极的作用。（眼科,2016, 25：294－298）     

候选基因多态性与糖尿病视网膜病变相关性的Meta分析

目的 候选基因多态性位点与2型糖尿病患者（type 2 diabetes mellitus，T2DM）的糖尿病视网膜病变（diabetes retinopathy，DR）相关性的Meta分析。设计 Meta分析。研究对象  T2DM的DR候选基因多态性的英文或中文文献。方法 在Pubmed（National Center for Biotechnology Information）、ISI（Web of Kowledge）、Embase和中国知网（China National Knowledge Internet，CNKI）4个数据库中，系统性检索、收集2019年1月1日以前以中文和英文发表的关于色素上皮源性因子（pigment epithelium derived factor，PEDF）、肿瘤坏死因子（tumor necrosis factor-α，TNF-α）和对氧磷酶-1（paraoxonase 1，PON1）三个基因的多态性位点与DR相关性的文献。采用Stata 12.0软件计算合并优势比（pooled odds ratio，pooled OR），分析组间异质性（Pheterogeneity）和发表偏倚（publication bias）。主要指标 OR值、组间异质性，发表偏倚。结果 共13篇研究纳入本Meta分析，包括2729例DR和3420例糖尿病对照。PEDF基因的 rs12948385位点（显性模型：OR=1.371，95%CI：1.072~1.755，P=0.012；等位基因模型：OR=1.266，95%CI：1.028~1.560，P=0.027）和PON1基因的L55M位点（隐性模型：OR=2.998，95%CI：1.282~7.010，P=0.011）与DR相关；TNF-α基因的rs1800629位点与PDR相关（等位基因模型：OR=1.291，95%CI：1.019~1.636，P=0.034）。结论  PEDF基因的 rs12948385位点、PON1基因的L55M位点可能与DR相关；TNF-α基因的rs1800629位点可能与PDR相关。     

人类白细胞抗原-B51与病葡萄膜炎的相关性研究

目的 探讨人类白细胞抗原(HLA)-B51与Behcet病葡萄膜炎间的相关性。 方法 应用微量淋巴细胞毒试验，对27例病患者和30例健康人的HLA-A和HLA-B抗原进行研究。应用聚合酶链式反应-序列特异性引物(PCR-SSP)技术测定HLA-B51抗原阳性的病患者和对照组人群中的HLA-B51等位基因(HLA-B*5101-B*5107). 结果 Behcet病患者和对照组HLA-B51的阳性频率分别为63%和16.7%［χ2=12.9，P＜0.001，Pc＜0.05,相对危险度(RR)=8.5 ］。在Behcet病患者中，葡萄膜炎的患病率为40.7%(11/27)；72.7%(8/11) Behcet病葡萄膜炎中存在HLA-B51(均为HLA-B*5101)。HLA-B51和HLA-B*5101与Behcet病葡萄膜炎存在弱相关性，但均未见统计学差异(分别为RR=2.07，χ2=0.759，P＞0.25；RR=2.67，χ2=1.395，P＞0.10)。 结论 提示HLA-B51(HLA-B*5101)是BehcetWT5”病的易感基因，并与葡萄膜炎有一定的相关性。 （中华眼底病杂志，2004，20：203-205）     

新型PCR-SSO方法在分析Eales病患者HLA-B基因型中的应用

目的通过使用新型聚合酶链反应-序列特异的寡核苷酸扩增分析（polymerase chain reaction restriction sequence specific oligonucleotide，PCR-SSO）方法分析Eales病患者及正常人群的人类白细胞抗原B组（human leucocyte antigen-B，HLA-B）基因型，了解这种方法的特点及其优越性。方法选取25例已确诊Eales病的患者作为研究组，自献血血库中选取与研究组患者年龄、性别无统计学差异的25例健康人作为对照组。抽取外周血提取DNA。使用新型PCR-SSO方法对DNA进行HLA-B基因位点的检测，得出结果，并进行统计学分析。结果分析结果可以同时显示基因型及对应的血清型，发现对照组中基因型HLA-B^＊ 15基因位点及对应的HLA-B62血清型明显高于研究组（P〈0．01）。结论PCR-SSO方法是一种先进的基因分型技术，具有其他基因分型方法无法比拟的优势，在科研工作中具有良好的应用前景。     

我国汉族Vogt-Koyanagi-Harada综合征患者人类白细胞抗原DQB1基因多态性研究

目的 探讨人类白细胞抗原(HLA)DQB1启动子和编码子在Vogt-Koyanagi-Harada(VKH)综合征发病中的作用.方法 88例汉族VKH综合征患者和88名正常对照者纳入本研究.VKH综合征患者中,男性41例,女性47例,发病年龄15～67岁,平均年龄(36±11)岁.正常对照者中,男性42例,女性46例,年龄24～68岁,平均年龄(41±19)岁.采用聚合酶链式反应-序列特异性引物(PCR-SSP)方法进行HLA-DQB1等位基因分型,聚合酶链式反应-单链构象多态性(PCR-SSCP)-克隆-测序法检测HLA-DQB1基因启动子区(HLA-QBP)等位基因.应用x2检验或Fisher精确概率法进行统计分析.结果 VKH综合征患者中HLA-DQB1*0401(0.318比0.045,x2=44.00,P=0.000,OR=9.8)和DQB1*0303(0.068比0.006,x2=9.67,P=0.002,OR=12.81)频率明显高于正常对照者,差异有统计学意义.而HLA-DQB1*0601(0.017比0.096,x2=10.39,P=0.001,OR=0.16)和HLA-DQB1*0302(0.063比0.193,x2=13.48,P=0.000,OR=0.28)在VKH综合征患者中出现的频率显著低于正常对照者,差异有统计学意义.VKH综合征患者HLA-DQB1基因启动子区-189C/A的C等位基因频率显著高于正常对照者(0.324比0.074,x2=45.92,P=0.000),而-227G/A等位基因频率低于正常对照者(0.011比0.108,x2=15.63,P=0.000).VKH综合征患者中易感等位基因的组合(-189C和HLA-DQB1*0401)频率明显高于正常对照者,正常对照者中抗性等位基因的组合(-227G和HLA-DQB1*0601)频率显著高于VKH综合征患者.结论 VKH综合征发病可能与HLA-DQB1启动子和编码区相互作用有关.     

病理性近视与HLA基因的关联

目的　研究病理性近视与 HL A基因的相关性 ,探讨其发病机制。方法　采用 PCR- RFL P方法对 12 1例病理性近视患者的 HL A 类基因 - DQB1位点的第二个外显子进行基因分析。计算 HL A- DQB1等位基因分布频率 ,确定相对危险率 (RR) ,并与正常人进行比较。结果　病理性近视患者 HL A- DQB1的 * 0 30 1,* 0 30 3等位基因频率显著高于在正常人中的分布 (Pc<0 .0 0 1) ;相对危险率 (RR)分别为 6 .946 4,5 .2 10 3。 * 0 6 0 1,* 0 6 0 2明显低于正常对照组 (P =0 .0 0 0 0 )。结论　 HL A- DQB1的 * 0 30 1和 * 0 30 3等位基因可能为病理性近视的易感基因 ,与发病有关 ;而 * 0 6 0 1,* 0 6 0 2可能为抵抗基因 ,具有保护作用。     

Profiling of human leukocyte antigens in Eales disease and tuberculosis

To analyze the association between Eales disease, histocompatibility leukocyte antigen alleles (HLA-A/B, HLA-DRB/DQB) and tuberculosis infection, and to explore susceptible genes and protective genes associated with Eales disease and tuberculosis infection in a population of Han nationals from Zunyi City in Guizhou Province, China. The subjects were analyzed by a case–control study consisting of three groups—Eales disease group (47 cases), pulmonary tuberculosis group (36 cases) and normal control group (100 cases). The Eales disease group was divided into four parts. Part one consisted of 12 patients who had suffered from pulmonary tuberculosis. Part two consisted of 27 patients who had not suffered from pulmonary tuberculosis. Parts three and four consisted of 27 patients with a positive purified protein derivative test and 12 patients with a negative test, respectively. DNA samples from 47 patients with Eales disease, 36 patients with pulmonary tuberculosis and 100 healthy people were detected by polymerase chain reaction with sequence-specific primers. The 59 HLA-A/B and HLA-DRB/DQB alleles from Eales disease were compared with those from tuberculosis and normal control, and a correlativity test of common susceptible genes was performed to analyze the potential relationship between Eales disease and pulmonary tuberculosis. The frequency distribution of HLA-A*02 alleles (OR 9.719, OR 95 % CI 4.377–21.580, P = 0.000) and HLA-B*07 (OR 11.605, OR 95 % CI 2.397–56.191, P = 0.001) in the Eales disease group was higher than in the normal control group, but the HLA-A*11 alleles (OR 0.495, OR 95 % CI 0.245–1.000, P = 0.048) were lower than in the normal control group, showing a significant difference. Compared with parts two and four, the frequency distribution of HLA-A*02, HLA-A*11 and HLA-B*07 alleles in parts one and three showed no significant difference (P > 0.05). HLA-A*A02, HLA-A*24, HLA-B*07 and HLA-DRB*16 alleles between the Eales disease, pulmonary tuberculosis and normal control group showed statistical significance (P < 0.05). HLA-A*24 alleles in the pulmonary tuberculosis group were lower than the Eales disease group (χ² 7.289, P = 0.007), but HLA-A*02 alleles showed no significant difference (P > 0.05) between the two groups. The results show that HLA-A*02 and HLA-B*07 may be genetic predisposing genes, but HLA-A*11 alleles may be protective genes of Eales disease, the HLA-A*02 allele may be a common susceptible gene of Eales disease and pulmonary tuberculosis. HLA-A*11 and HLA-A24 alleles are protective genes of Eales disease and pulmonary tuberculosis, respectively. In summary, the frequency distribution of susceptible genes of Eales disease and pulmonary tuberculosis in a population of Han nationals from Zunyi City in Guizhou Province, China showed no significant difference.     

Association of HLA with Vogt-Koyanagi-Harada syndrome in Koreans

PURPOSE: To study the distribution of human leukocyte antigen HLA-A/B antigens and HLA-DR/-DQ/-DP alleles and to investigate the immunogenetic background of Korean patients with Vogt-Koyanagi-Harada (VKH) syndrome and clinical course with different types of HLA. METHODS: Human leukocyte antigen typings were performed in 18 Korean patients with VKH syndrome and in 128 healthy control subjects. HLA-A/B loci serologic typing was performed according to the standard microlymphocytotoxicity technique. DNA was extracted through the salting out method, and HLA-DR phenotyping and HLA-DR4, HLA-DQ, and HLA-DP subtyping were performed with the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. RESULTS: Among HLA-A/B antigens typed by the standard microlymphocytotoxicity method, the frequencies of HLA-A31 (RR = 6.1, P<1x10(-2)) and HLA-B55 (RR = 15.8, P<.05) were significantly increased in the patient group compared with the control group. Among HLA-DR/-DQ/-DP alleles subtyped by DNA methods, the frequencies of HLA-DRB1*04 (RR = 45.1, P<1x10(-7)) and HLA-DRB1*07 (RR = 3.2, P<.05) were significantly increased. However, significant decreases in HLA-DRB1*08 (RR = .1, P<.05), HLA-DRB1*13 (RR = .1, P<.05), and HLA-DRB1*14 (RR = .1, P<.05) frequencies were observed. The result of HLA-DR, HLA-DQ, and HLA-DP subtyping showed the significant increase in DRB1*0405 (RR = 45.1, P<1x10(-7)), DQA1*0302 (RR = 12.0, P<1x10(-4)), DQB1*0303 (RR = 5.0, P<1x10(-2)), DQB1*0401 (RR = 18.9, P<1x 10-6), and DPB1*0501 (RR = 3.8, P<.05). However, significant decreases in DQA1*0101 (RR = .1, P< .05), DQA10102 (RR = .1, P<1x10(-2)), DQA1*0103 (RR = .1, P<.05), DQA1*0501 (RR = .1, P<1x10(-2)), DQB1*0301 (RR = .1, P<.05), DQB1*0601 (RR = .1, P<.05), DPB1*0201 (RR = .3, P<.05), and DPB1*0401 (RR = .1, P<.05) frequencies were also observed. In patients with DRB1*0405 itself or HLA-DRB1*0405-DQA1*0302-DQB1*0401 haplotype, a reduction in visual acuity and ocular complications was common. CONCLUSIONS: These results suggest that HLA-DRB1*0405 itself or HLA-DRB1*0405-DQA1*0302-DQB1*0401 haplotype is greatly increased and may play the most important role in the development and the clinical course of VKH syndrome in Korean patients.     

Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome

PURPOSE: To identify genetic markers for the tubulointerstitial nephritis and uveitis (TINU) syndrome by using human leukocyte antigen (HLA) genotyping. METHODS: Eighteen patients who had TINU syndrome were evaluated at three institutions. Typing of class I and II genes was performed by using DNA-based techniques. RESULTS: Significant associations were found with HLA-B14 (6/18 patients, 33.3%; control subjects, 5.5%; P = 0.0003; relative risk [RR] = 8.5), HLA-DQA1*01 (17/18 patients, 94.4%; control subjects, 46.6%, P = 0.0001; RR = 19.5), HLA-DQA1*0101 (14/18 patients, 77.8%; control subjects 22.2%; P < 0.0001; RR = 12.2), HLA-DQB1*05 (14/18 patients, 77.8%; control subjects 17.7%; P < 0.0001; RR = 16.3), HLA-DQB1*0501 (13/18 patients, 72.2%; control subjects 12.9%; P < 0.0001; RR = 17.6), HLA-DRB1*01 (14/18 patients, 77.8%; control subjects, 12.1%; P < 0.0001; RR = 25.5), and HLA-DRB1*0102 (13/18 patients, 72.2%; control subjects, 1.6%; P < 0.0001, RR = 167.1). The HLA haplotype most frequently identified in the study patients was HLA-DQA1*01/DQB1*05/DRB1*01 (13/18 patients, 72.2%). CONCLUSIONS: TINU syndrome is strongly associated with HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01. The association with HLA-DRB1*0102 is one of the highest reported for any disease. Because these genes are in linkage disequilibrium, the role of the individual alleles is difficult to assess. Based on the results of the present study and on previously reported HLA associations in patients with TINU syndrome, the alphabeta dimer encoded by HLA-DQA1*01/DQB1*05 may be particularly important in conferring risk for development of this disease.     

Human leukocyte antigen serologic and DNA typing of Beh?et's disease and its primary association with B51.

Ninety Japanese patients with Beh?et's disease (BD) were typed for human leukocyte antigen (HLA)-DRB1, -DQA1-, -DQB1, and -DPB1 alleles by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and for HLA-A, -B, -C, -DR, and -DQ antigens by conventional serologic typing. Serologic HLA typing showed a remarkably significant increase of HLA-B51 and a significant decrease of HLA-DQw1 in the patients with BD, especially those with ocular lesions including complete type, as compared with the control group (for B51, chi-squared = 46.75, P corrected < 0.001, relative risk [RR] = 7.9; for DQw1, chi-squared = 12.10, P corrected < 0.01, RR = 0.4). By PCR-RFLP genotyping, no significant difference was revealed in any class II alleles between the patient and the control groups in the corrected P value test, but P value analysis showed the significantly high frequency of DRB1*0802 and the significantly low frequencies of DQA1*0103, DQB1*0601, and DQB1*0501. No significant difference was observed in any DPB1 alleles by either P value analysis. These results indicated that the primary and primordial gene(s) responsible for the susceptibility to BD, especially related to ocular lesions, were not located in the HLA class II gene region but were in or very close to the HLA-B locus in the class I region. They also suggested the possibility that BD was a symptom complex associated with some independent diseases.     

Frequencies of human leukocyte antigen alleles and haplotypes among Japanese patients with age-related macular degeneration

Purpose

Stem cell therapy is a potential treatment for retinal disorders. We are currently exploring treating HLA matched patients of age-related macular degeneration (AMD) by using allogenic retinal pigment epithelium cells derived from induced pluripotent stem cells (iPS-RPE) from human leukocyte antigen (HLA) homozygote donors. The purpose of this study was to investigate the frequency of HLA class I and II alleles and haplotypes in Japanese patients with AMD.

Study design

Cross-sectional observation clinical study.

Methods

A total of 138 consecutive patients diagnosed with neovascular AMD (mean age, 76.0?±?7.8 years, 105 men) and 300 controls were included in the study. The frequencies of HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 alleles were determined using illumina MiSeq platform. Frequencies of HLA alleles at six loci in patients with AMD were compared with those of the controls.

Results

The alleles with the highest prevalence at each locus were A*24:02 (29.7%), B*52:01 (15.5%), C*12:02 (16.1%), DRB1*09:01 (19.1%), DQB1*06:01 (23.2%), and DPB1* 05:01 (40.5%). There were no significant associations between the HLA alleles and AMD. The most common haplotype was A*24:02-B*52:01-C*12:02-DRB1*15:02-DQB1*06:01-DPB1*09:01, with a 9.8% genetic frequency among all haplotypes, detected in 18.8% of the patients.

Conclusion

The genotype of HLA in patients with AMD was not different from that in the Japanese control population. Thus, therapy with iPS-RPEof the most frequent HLA haplotype could be a feasible alternative for AMD in a wider population.

     

HLA-DRB and HLA-DQB loci in the genetic susceptibility to develop glaucoma in Mexicans.

PURPOSE: Glaucoma is a clinically heterogeneous disease with a pathophysiology that may include genetic susceptibility, possibly associated with an immunologic disorder. The aim of this study was to determine whether the DNA polymorphisms located in the HLA-DRB1 and HLA-DQB1 genes show a specific association pattern in Mexican mestizo patients with primary open-angle glaucoma. METHODS: This was a cross-sectional, case-control, multicenter study. We analyzed the HLA-DRB1 and DQB1 loci of 81 Mexican mestizo nonrelated patients with primary open-angle glaucoma and 98 healthy ethnic matched control subjects. Patients were diagnosed clinically and by visual fields examination. HLA typing was performed by PCR-SSO reverse dot blot. RESULTS: We documented increased frequencies of HLA-DRB1*0301, DRB1*1101, DRB1*0701, DRB1*1402, DQB1*0302, and DQB1*0301; however, none of them were significantly different from normal control subjects. Haplotype analysis showed that the HLA-DRB1*0407-DQB1*0302 haplotype is significantly increased in patients compared with control subjects (P = .0001). CONCLUSIONS: The haplotype HLA-DRB1*0407-DQB1*0302 is common among Mexican mestizo (haplotype frequency = 0.102), and it was increased in our patients (haplotype frequency = 0.259, P = .0001). This may reflect an independent association of this haplotype with the disease as the result of linkage disequilibrium or the influence of a neighboring gene. The pathophysiology of this illness is uncertain, and further studies are needed regarding the genetic susceptibility to develop primary open-angle glaucoma.     

Next-Generation HLA Sequence Analysis Uncovers Shared Risk Alleles Between Clinically Distinct Forms of Childhood Uveitis

PurposeClassical alleles of the human leukocyte antigen (HLA) complex have been linked to specific entities of pediatric noninfectious uveitis, yet genetic predisposition encoded by the HLA super-locus across the patient population remains understudied.MethodsWe performed next-generation full-length sequencing of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1 in 280 cases. Dense genotype data from 499 Dutch controls from Genome of the Netherlands were imputed using an HLA-specific reference panel (n = 5225 samples from European ancestry). Cases and controls were compared using logistic regression models adjusting for sex.ResultsIn total, 179 common and rare alleles were detected. Considering all cases and controls, HLA-DQB1*04:02 and HLA-DRB1*08:01 were identified as the principal HLA association, which was mainly driven by 92 cases with juvenile idiopathic arthritis-associated uveitis (JIA-U). The HLA-DQB1*04:02-HLA-DRB1*08:01 haplotype was also the primary association for the phenotypically similar idiopathic chronic anterior uveitis without arthritis (CAU). Also, HLA-DQB1*05:03 was an independent risk allele for CAU, but not in JIA-U. Analysis of 185 cases with other forms of uveitis revealed HLA-wide associations (P < 2.79 × 10⁻⁴) for HLA-DRB1*01:02, HLA-DRB1*04:03, and HLA-DQB1*05:03, which could be primarily attributed to cases with panuveitis. Finally, amino acid substitution modeling revealed that aspartic acid at position 57 that distinguishes the risk allele HLA-DQB1*05:03 (for CAU and panuveitis) from nonrisk alleles, significantly increased the binding capacity of naturally presented ligands to HLA-DQ.ConclusionsThese results uncovered novel shared HLA associations among clinically distinct phenotypes of pediatric uveitis and highlight genetic predisposition affecting the antigen presentation pathway.     

Vogt—Koyanagi—Harada综合征与人类白细胞抗原—DQA1和—DQB1基因 …

目的 探讨人类白细胞抗原－ＤＱＡ１和－ＤＱＢ１（ｈｕｍａｎ ｌｅｕｋｏｃｙｔｅ ａｎｔｉｇｅｎ－ＤＱＡ１ ａｎｄ ＤＱＢ１,ＨＬＡ－ＤＱＡ１ａｎｄＤＱＢ１）基因与沃洛特－小柳－原田综合征（Ｖｏｇｔ－Ｋｏｙａｎａｇｉ－Ｈａｒａｄａｓｙｎｄｏｍｅ,ＶＫＨ）遗传易感的相关性。方法 应用聚合酶链式反应－序列特异性引物（ｐｏｌｙｍｅｒａｓｅｃｈａｉｎｒｅａｃｔｉｏｎ－ｓｅｑｕｅｎｃｅｓｐｅｃｉｆｉｅｐｒｉｎ