摘要
背景沃格特—小柳—原田综合征(Vogt—Koyanagi—Harada syndrome，VKH)发病机制尚不清楚，目前认为与HLA—Ⅱ类基因复合体密切相关。1994年Islam和Shindo等的研究结果认为HLA—DRB1~*0405、DQB1~*0401可能对VKH的易感性起重要作用，我国肖天林、刘勤、张美芬也分别报道了中国南方及北方汉族VKH患者与HLA—Ⅱ类基因复合体编码区具有类似的相关性。但是这些文献对HLA-DQB1等位基因型别的研究方法集中为PCR—SSO和PCR～RFLP，较为费时，操作繁杂；同时尚未见有关VKH患者与HLA—DQB1调控区关系的报告。
目的检测我国北方汉族VKH患者HLA—DQB1编码区和启动子区基因型，分析编码区、启动子区、临床表现的相互关系。
方法收集我国北方汉族VKH患者外周血88例，应用PCR-SSP法和PCR-SSCP-克隆-测序法分别检测HLA-DQB1编码区和启动子区基因型。
结果符合入选标准的VKH患者88例，男性41人，占46.59％，女性47人，占53.41％。发病年龄15.0—67.0岁，平均36.3±11.4岁。
HLA—DQB1编码区多态性结果显示，VKH患者／正常人HLA—DQB1各亚型的频率分别为~*0401为31.82％／4.55％，~*0201为17.61％／15.34％，~*0301／~*0304为17.05％／22.73％，~*0602为12.50％／11.93％，~*0303为6.82％／0.57％，~*0302为6.25％／19.32％，~*0402为1.70％／1.14％，~*0502为1.70％／3.98％，~*0601为1.70％／9.66％，~*0501为1.14％／3.41％，~*0503为1.14％／2.27％，~*0604为0.57％／2.84％，~*0603为0.0％／2.27％。VKH患者中HLA—DQB1~*0401(x~2=44.00，P=0.000，OR=9.8)和DQB1~*0303(x~2=9.67，P=0.002，OR=12.81)出现频率高于对照组，差异有统计学意义。而HLA—DQB1~*0601(x~2=10.39，P=0.001，OR=0.16)和HLA—DQB1*0302(x~2=13.48，P=0.000，OR=0.28)在VKH患者中出现频率显著低于对照组，有统计学意义。HLA—DQB1~*0401阳性与阴性VKH患者之间临床表现比较，如年龄、眼外表现、眼部表现及视力预后无统计学意义。
HLA—DQB1上游启动子区(QBPl)／调控区(URR)多态性结果显示，正常人和VKH患者HLA—DQB1~*上游启动子区共计有16种SSCP带型，患者集中在2A，4A，4B，4C；正常人集中在2B，3D，分布较为分散。纯合子为两条带，正常人和患者带型出现频率有显著差异(x~2=526.5，P=0.037)；杂合子为3条带(x~2=5.0，P=0.009)或4条带(x~2=61.0，P=0.000)，正常人和患者带型间出现频率有显著统计学差异。对典型带型对应的目的片段连接质粒、转染感受态细胞、增菌培养，并进行DNA序列测序，结果与已命名的序列比对，归为5种QBP1s，与对照组比较，HLA—DQB1一QBP1~*0601频率显著降低(x~2=11.68，P=0.001)。同时发现可能存在12种SNPs，即—21 ACT／———，—40 G／A，—94 G／A，—103 G／A，—151 G／A，—171 G／A，—173 T／C，—182—／A，—182———／AAA，—189 C／A，—214 G／A，—227 G／A，其中—189 C／A在病例组中的分布频率显著高于对照组(x~2=45.92，P=0.000)，而—227 G／A频率低于对照组(x~2=15.63，P=0.000)。
综合分析VKH患者调控区和编码区的关系，HLA—DQB1*0401阳性VKH患者51人，阴性37人，其QBP1区PCR—SSCP结果显示：2条带型(x~2=36.0，P=0.000)和4条带型(x~2=48.0，P=0.000)在两组间的频率比较有统计学意义，而3条带型两组间的患者均较少，未发现有统计学差异(x~2=0.3，P=0.564)；编码区HLA—DQB1~*0401，—DQB1~*0601以及上游调控区序列QBP1~*0601之间存在一定的累积效应；单核苷酸多态性—189 C／A和—227 G／A与HLA—DQB1~*0401和HLA—DQB~*0601之间也存在累积效应。
结论1)HLA—DQB1"0401和DQB1*0303与VKH遗传易感性密切相关，而HLA—DQB1*0601和DQB1*0302则与VKH遗传抵抗性密切相关，HLA—DQB1*0401同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。3)VKH患者启动子区存在12种SNPs，其中—189 C／A是其易感SNP，而—227 G／A是抗性SNP，HLA—QBP1*0601是抗性等位基因；4)上游调控区等位基因—QBP1*0601和SNPs(—189 C／A，—227 G／A)与编码区—DQB1*0401和—DQB1*0601之间具有累积效应。
Vogt—Koyanagi—Harada syndrome(VKH) is featured as bilateral, diffuse, granulomatous panuveitis often associated with alopecia, vitiligo, poliosis, tinnitus dysacusis and meningeal symptoms. Pigmented populations, such as Mongolian ancestry, Aficans and some Mestizo were often affected for the auto- immunological mechanisms against the pigment cells in the skin, meninges, inner ear and ocular tissues. The Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) plays an important role on its course. Polymorphisms of HLA in patients with VKH have been reported especially in the past 10 years. HLA—DR4 by serology, HLA—DRBI~*0405, DQBI~*0401 by PCR—SSO or RFLP were reported to be associated with VKH in various degree in Japanese, Chinese, Mexico and American Mestizo, Korea, ect. However no one focuses on the upper regulatory regions(URRs) or promoter regions(QBP) of HLA- DQB molecules and combinatory analysis between coding region and QBPs for VKH syndrome. In our study 88 North Chinese Han patients with VKH matched with 88 healthy controls were admitted. Polymorphism of coding region and upper regulatory region for HLA—DQB1 were investigated by PCR- SSP and PCR- SSCP respectively. Relationships among HLA--DQB1 alleles and clinical manifestations, association among coding regions and promoter of HLA--DQB1 were analyzed.
12 of 13 already known HLA—DQB1 Alleles were detected in patients with VKH by PCR—SSE The most frequent allele was HLA—DQBI~*0401(31.82%). It was in strong association with VKH syndrome as compared to the healthy controls (31.82% vs. 4.55%,χ~2=44.00, OR=9.8). So was for HLA—DQBl~*0303 (6.82%vs. 0.57%,χ~22=9.67, OR=12.81). On the contrary, the frequency of HLA—DQB1~*0601 (1.70% vs. 9.66%,χ~2=10.39, P=0.001, OR=0.16)and HLA—DQB1~*0302 (6.25% vs. 19.32%,χ~2= 13.48, P=0.000, OR=0.28) were lower in patients with VKH than that of controls, the differences were statistically significant. We found no relationships among HLA—DQBI~*0401 and clinical manifestations such as age of onsets, visual acuity, cataract, complicated glaucoma, exudative retinal detachment.
By PCR—SSCP, 16 representative gels on denatured polyacrylamide gel electrophoresis for all subjects were found. The types of gels among patients and controls were significantly different in 2—, 3—, 4—band gels. After ligation with plasmids, transfection into recipient cells and sequencing of the culturing bacteria, the sequences of the corresponding fragments were confirmed. Matched by already known HLA--DQB1 promoters sequences(QBP1), five kinds of QBPls, ~*0201, ~*0301, ~*0302, ~*0401 ~*06011, were summed up. The frequency of HLA--DQB1 promoter(QBP1) ~*0601 was significantly lower than that of controls (χ~2=11.68, P=0.001). 12 SNPs, including—21 ACT/———,—40 G/A,—94 G/A,—103 G/A,—151 G/A,—171 G/A,—173 T/C,—182—/A,—182———/AAA,—189 C/A,—214 G/A and—227 G/A, were discovered. Among them, the frequency of—189 C/A in patients with VKH was significantly higher than that in controls(χ~2= 45.92, P=0.000). On the contrary the frequency of—227 G/A in patients with VKH was significantly lower than that in controls(χ~2= 15.63, P=0.000).
Combinational analysis of the relationships among the coding regions and promoters was established. The cumulative effects among HLA—DQBI~*0401,—DQBI~*0601 and QBP1~*0601 were found. The same phenomenons were found among—189 C/A,—227 G/A, HLA--DQB1~*0401 and HLA—DQB~*0601. These findings matched with the law of cumulative effects of multiple genotypes.
It can be concluded: 1) Alleles of HLA—DQB1~*0401 and HLA--DQB1~*0303 were susceptible to VKH syndrome, 2) HLA—DQB1~*0601 and HLA—DQB1~*0302 were resistant to VKH syndrome. 3) PCR--SSP was a rapid method to identify the HLA—DQB1 alleles and can be used as routine. 4) QBPI~*0601 was the resistant gene in patients with VKH. 5)—189 C/A and—227 G/A were the susceptible and resistant SNPs of QBP1 in patients with VKH respectively. 6) With respective corresponding coding alleles (HLA—DQB1~*0401 and ~*0601), QBP1~*0601,—189 C/A and—227 G/A play accumulative effects on patients with VKH.
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