【作者】 葛宏松；

【导师】 杨森； 张学军；

【作者基本信息】 安徽医科大学 ， 皮肤性病学， 2003， 硕士

【摘要】 银屑病是一种慢性、炎症性增生性皮肤病，其发病具有一定的遗传因素。而寻常型银屑病占银屑病总发病率的90％以上。从世界的角度来讲，各民族的发病率从0％～3％表现广泛的差异，美洲及欧洲发病约为2％，而在中国的发病率为0.123％，我国的银屑病患者约超过300万。在我们最近的研究中，发现我国银屑病患者的一级或二级亲属的患病率分别为7.24％、0.95％，高于普通人群的患病率。人群及双生子研究明显地表明遗传因素在银屑病的发病中起重要作用。在过去几年的研究中，许多研究小组把目光集中在银屑病发病的分子遗传学基础上。更多集中在6p21.3银屑病易感基因位点，该区域含有MHC。到目前为止世界各地科学家报道了关于银屑病患者发病相关HLA抗原有HLA-A1，A2，A30，B13，B17，B37，B^*57，B39，B46，Cw6，Cw7，Cw9，Cw11，DQA1^*0201，DQB1^*0303，DRB1^*0701／02，DRB1^*1401。在过去的20年研究中发现HLA-A1，B13，B17，Cw4，Cw6，DQB1^*0602，DRB1^*0701／02在中国汉族银屑病患者显著增高。所谓连锁不平衡是指单倍型频率实际观察值显著地大于或小于理论值，一些银屑病患者的危险或保护单倍型在不同民族中被确认。 目的 探讨中国汉族人寻常型银屑病与HLA单倍型相关性。方法 利用聚合酶链反应-序列特异性引物（PCR-SSP）法，对138名银屑病患者及149名健康对照进行PCR反应，分析各等位基因及单倍型的分布情况。结果 （1）HLA-A^*26(26.09％vs12.08％，OR=3.42，P＜10^-6，pc＜10^-5)，-B^*27(17.03％vs1.01％，OR=25.14，P＜10^-7，Pc＜10^-7)，-Cw^*0602(15.58％vs5.03％，OR=4.04，P＜10^-5，Pc＜10^-2)，-DQA1^*0104(19.93％vs9.04％，OR=2.86，P＜10^-5，Pc＜10^-3)，-DQA1^*0201(22.40％vs10.74％，OR=2.98，P＜10^-5，Pc＜10^-3)，-DQB1^*0303(18.12％vs9.73％，OR=4.65，P＜10^-7，Pc＜10^-6)，-DRB1^*0701／02(26.09％vs9.73％，OR=4.51，P＜10^-7 pc＜10^-7)等位基因在银屑病患者中增高，且有明显的统计学意义；HLA-B^*57（2.90％vs0.34％，OR=9.11，P＜0.013，Pc＜0.234）、安徽医科大学硕士学位论文DQBI*0201（19.20%vsl2.73%，OR=1.81，P<0.019，Pe<0.36）等位基因的频率在寻常型银屑病患者中轻度升高，但无统计学意义。（2） HLA一Cw*0304（5 .07%vs14.43o，0，o卜0 .25，P<10一，，Pe<10一2），一oQAI*0501（5.790，0vs一4.090，0，o卜2‘99，P<o，0047，Pc<0.047）在银屑病患者中显著性下降，相对与正常对照组差异有统计学意义。HLA一AZ（2.54%vs6.38%，OR=0.37，P<0.023，Pe<0.552）等位基因频率在寻常型银屑病患者中轻度降低，无统计学意义。（3）在I类等位基因中HLA一B*27分别与HLA一A*26，Cw*0602间连锁不平衡。同是证实了HLA一DRBI*070 1/02与HLA一B*27、一DQAI*0104，一DQAI*02俱，以及DQBI*0303间明显的连锁不平衡。而在HLA一DQAI与DQBI两个座位间，HLA一DQAI*0201一DQBI*0303.一DQAI*0 1 04一DQAI*0303的连锁不平衡值明显大于0.02，以上基因间的连锁在银屑病患者相对于正常对照均有统计学意义。（4）HLA一A*26一B*27，DQAI*0201一DQBI*0303，DQAI*0104一DRBI*0701/02，DQBI*0303一DRBI*0701/02，A*26一DQAI*0201一DQBI*0303一DRBI*0701仅与I型银屑病患者相关，而其它相关单倍型频率在I型及H型银屑病患者中均升高。（5）除DQBI*0303一DRBI*0701/02仅与男性银屑病患者相关外，其它相关单倍型在不同性别间无显著差异。结论本研究证实了相对于其他民族而言，中国汉族人寻常型银屑病存在特定的HLA相关等位基因及单倍型。更多还原

【Abstract】 Background Psoriasis is a common chronic inflammatory and hyperproliferative skin disease with a strong genetic component. Psoriasis vulgaris is the most common type (>90%). Prevalence rates of psoriasis ranges from 0 to 3% and shows a wide variability between different ethnic groups [1] The estimated prevalence rate of psoriasis is about 2% in the USA and northern Europe [2] In China, psoriasis affects 0.123% of the population and there have been more than 3 million cases reported since 1984[3]. In our recent studies, prevalence rate of psoriasis vulgaris in first-degree and second-degree relatives of the proband with psoriasis was 7.24% and 0.95% respectively, which were higher than that in general population [4]. A significant genetic component to psoriasis susceptibility has long been supported by observations of family disease clustering, elevated concordance rates amongst monozygous twins [5]. Over the last few years, a number of research groups have pursued major studies investigating the molecular genetic basis of psoriasis. Particular attention is given to the genetic analysis of the major histocompatibilty complex on human chromosome 6, a region subject to intense scrutiny [6,7]. Up to now, various HLA associations have been reported. There are increased frequencies of class I antigens HLA-A1, A2, A30, B13, B17, B37, B*57, B39, B46, Cw6, Cw7, Cw9, Cw11, and class II antigens DQA1*0201,DQB1*0303, DRB1*0701/02,DRB1*1401. [8,9,10,11] This relationship, however, tends to vary between patients of different racial and ethnic backgrounds [12,13l. During the past over 20 years, it was reported that the frequencies of several HLA antigens including Al, B13, B17, Cw4, Cw6 and DQB 1*0602, DRB 1*0701/02 were increased in PV in Chinese Hans [14]. In linkage disequilibrium analysis, certain alleles occur together more frequently than expected by chance; some risk or protective haplotypes were reported in different ethnical groups l19’26-28-29’30-’1^ Objective To identify special haplotypes in Chinese Hans that may contribute to the genetic susceptibility to PV. Material and Methods One hundred and thirty-eight psoriasis vulgarispatients and 149 non-psoriatic controls were typed for HLA- A, B, C, DQA1, DQB1, DRB1 by using the polymerose chain reaction sequence-specific primer (PCR-SSP) technique. Results (l)The allele frequencies of HLA-A*26 (26.09%vsl2.08%,OR=3.42,P<10-6,Pc<10-5) ,-B*27 (17.03%vsl.01%,OR=25.14,P<10-7,Pc<10-7) ,-Cw*0602 (15.58%vs5.03%,OR=4.04,P<10’5,Pc <10-2),-DQAl*0104(19.93%vs9.04%,OR=2.86,P<10-5,Pc<10-3),-DQAl*0201 (22.40%vsl0.74 %,OR=2.98,P<10-5,Pc<10-3), DQB1*0303 (l8.l2%vs9.73%,OR=4.65,P<10-7,Pc<lO-6),DRBl*0701 702 ( 26.09%vs9.73%,OR=4.51,P<10"7,Pc<10~7 ) were significantly increased in PV patients, however,HLA-B*57 (2.90%vs0.34%,OR=9.11 ,P<0.013 ,Pc<0.234 ), DQB1 *020 (19.20%vs 12.73%, OR=1.81,P<0.019,Pc<0.36 ) were slightly increased in psoriasis patients without statistical significance.HLA-Cw*0304(5.07%vsl4.43% OR=0.28, P<10-5,Pc<10-2), -DQA1*0501 (5.79%vsl4.09%,OR=2.99,P<0.0047,Pc<0.047) were found to be negatively associated with psoriasis vulgaris,while HLA-A2 was slightly decreased in psoriasis patients compared with normal controls. (2) Significant linkage disequilibrium between HLA-A*26 and B*27, and between B*27 and Cw*0602 were found by the analysis of two-locus haplotypes in the HLA-class I alleles. HLA-DRB1*0701/02 was also found to have significant linkage disequilibrium with B*27, DQA 1*0104, DQA 1*0201, and DQB 1*0303. DQA 1-DQB 1 haplotype, two of the combinations: DQA 1*0201 -DQB 1*0303,DQA1*0104-DQA 1*0303 were exclusively associated with PV patients. From these results, two haplotypes, HLA-A*26 -B*27 -Cw*0602, DRB1*0701 -DQA1*0201 -DQB1*0303, A*26 -DRB1*0701/02 -DQA1*0201 -DQB1*0303 were suggested to be associated with PV in Chinese hans (3) HLA-A*26-B*27, B*27-Cw*0602, DQA1*0201-DQB1*0303, DQA 1 *0104-DRB1 *0701/02, DQB 1 *0303-DRB 1 *0701 /02 and A*26-DQA 1 *0201 -DQB 1 *0303-DRB 1*0更多还原