HLA-Ⅱ类基因与中国汉族人白癜风及其临床特征的相关性研究

发布时间：2018-08-03 07:04

【摘要】：研究背景：白癜风是一种常见的色素脱失性皮肤疾病,通常由于皮肤和毛发内的黑色素细胞选择性破坏所致。白癜风的发病率范围由0.1%到2.9%,在不同种族和地域之间存在显著的差异性。该病虽然不会危及生命,但对患者的身心健康造成巨大的负面影响。白癜风多发生于儿童或青年,约一半患者于20岁以前发病,因此通常以白癜风发病年龄20岁为界,将其分为早发型白癜风(Early-onset vitiligo)和晚发型白癜风(Late-onset vitiligo).临床和流行病学调查研究均表明白癜风遵循一种多基因遗传模式。白癜风发病机制目前尚未明确,目前提出的一些相关假设主要包括黑素细胞自身破坏学说、生物化学、神经起源学说、自身免疫和遗传学说。在过去的十多年,自身免疫学说主要源于在流行病学研究中发现白癜风患者及其亲属常伴发其他自身免疫性疾病,如自身免疫性甲状腺病、风湿性关节炎、银屑病、成人胰岛素依赖型糖尿病、恶性贫血、阿狄森氏病和系统性红斑狼疮。人类白细胞抗原(HLA)是目前公认的在各类自身免疫性疾病的易感性中发挥重要作用的影响因素,与白癜风发病相关的部分遗传因素也主要集中于HLA系统。既往在不同人群的白癜风研究中,多数报道其发病与HLA-II类基因相关,但很少有研究可获得一致的关联证据,可能与遗传效应微弱,基因间、基因与环境间复杂的交互作用,人群分层或不同人群间的遗传差异性有关。通过对以往研究结果的重新分析,发现在HLA-Ⅱ类基因中,DRB1*07一直显示与中国汉族人白癜风有显著相关性。有趣的是,有报道发现HLA-DR在白癜风皮损周围的表皮内表达异常,提示其可能在HLA-II类基因限制性黑素细胞的死亡中发挥作用。最近,也有一些研究发现携带HLA-II类基因／单倍型的个体,其白癜风的发病年龄更早,更易伴发自身免疫性疾病,家族史的发生率更高。目的：(1)进一步探寻HLA-II类基因在中国汉族人群中与白癜风的相关性。(2)评估HLA-II类基因对中国汉族人白癜风各临床特征的遗传效应。方法：采用多聚酶链反应(PCR)／序列特异引物的方法,探寻HLA-DRB1*07等位基因在1178例彼此间无血缘关系的白癜风患者和1743例健康对照中的分布情况,观察HLA-DRB1*07等位基因阳性的白癜风患者和HLA-DRB1*07阴性患者间临床特征的差异性。结果：(1)白癜风病例中HLA-DRB1*07阳性的比例较对照中HLA-DRB1*07阳性的比例显著增高(40.75％vs.25.83％,OR:1.97,95％CI1.68-2.31,P=2.13×10-17).病例和对照中DRB1*07阳性等位基因频率分别为0.20和0.13。在所有白癜风病例中,有480例为DRB1*07日性,剩余的698例患者则为DRB1*07阴性。在病例组中,DRB1*07日性患者的平均年龄为25.57±14.45岁,而DRB1*07阴性患者的平均年龄为27.43±14.71岁(P=0.031)。男女性别比例在白癜风病例的DRB1*07阳性和阴性两组间未见显著差别(P=0.099).(2)HLA-DRB1*07阳性的白癜风患者比DRB1*07阴性患者的发病年龄更早。HLA-DRB1*07阳性的白癜风患者的发病年龄中位数为17.00±16.00岁,HLA-DRB1*07阴性的白癜风患者的发病年龄中位数为19.00±18.00,两者之间存在显著性差异(P=0.004)。在DRB1*07阳性患者中,早发型白癜风的频率也较阴性患者中显著增高(65.14％vs.55.59％,P=0.001,OR=1.49,95％CI1.17-1.90).(3)DRB1*07阳性的白癜风患者较DRB1*07阴性患者的家族史发生率更高。在DRB1*07阳性的白癜风患者中,约30.8%具有家族史,而仅有23.6%的DRB1*07阴性患者有家族史(OR=1.44.95％CI1.11-1.87,P=0.006).(4)与DRB1*07阴性的白癜风患者相比,DRB1*07阳性患者患自身免疫性疾病的频率较高(4.0%vs32%),然而,两组间的频率差别未达到统计学的显著性水平(OR=1.27,95％CI0.68-2.37,P=0.458) 结论：(1)HLA-II类基因与中国汉族人白癜风存在显著的关联性。(2)中国汉族人白癜风HLA-DRB1*07阳性的患者与HLA*DRB1*07阴性患者的临床特征有明显的差异,HLA-DRB1*07阳性白癜风患者较阴性患者的发病年龄更早,家族史发生率更高。(3)本研究提示自身免疫易感性相关的遗传因素可能在白癜风的一些临床特征或临床亚型的发病机制中发挥重要作用。
[Abstract]:Background: vitiligo is a common pigmented dermatosis skin disease usually caused by selective destruction of melanocytes in the skin and hair. The incidence of vitiligo is from 0.1% to 2.9%, and there is a significant difference between different races and regions. There is a huge negative impact. Vitiligo occurs mostly in children or young people. About half of the patients are at the age of 20 years of age, so they are usually divided into early onset vitiligo (Early-onset vitiligo) and late onset vitiligo (Late-onset vitiligo). Clinical and epidemiological studies all indicate vitiligo follows. A multi gene genetic model. The pathogenesis of vitiligo is not yet clear. Some of the relevant hypotheses are mainly included in the theory of melanocyte self destruction, biochemistry, neural origin, autoimmunity and genetics. In the past more than 10 years, the autoimmunity theory mainly originated from the discovery of vitiligo in epidemiological studies. People and their relatives often accompany other autoimmune diseases such as autoimmune thyroid disease, rheumatoid arthritis, psoriasis, adult insulin dependent diabetes, malignant anemia, Addison's disease and systemic lupus erythematosus. Human leukocyte antigen (HLA) is currently recognized in the susceptibility of various autoimmune diseases. Some of the genetic factors associated with the pathogenesis of vitiligo are also mainly concentrated in the HLA system. In the previous study of vitiligo in different populations, most of them reported that the disease was associated with HLA-II genes, but few studies could obtain consistent evidence, which might be complicated with genetic effects, genes, and the complexity of the environment. Interaction, population stratification or genetic diversity among different populations. Through reanalysis of previous studies, it was found that in the HLA- class II gene, DRB1*07 has been shown to have a significant correlation with vitiligo in Chinese Han people. Interestingly, it is reported that the expression of HLA-DR is abnormal in the epidermis of the skin lesions of vitiligo, suggesting that there is an abnormal expression in the epidermis of the skin of vitiligo. It may play a role in the death of HLA-II gene restrictive melanocytes. Recently, some studies have found that individuals carrying HLA-II gene / haplotype are older, more susceptible to autoimmune diseases, and higher incidence of family history.
Objective: (1) to further explore the correlation between HLA-II gene and vitiligo in Chinese Han population. (2) to evaluate the genetic effect of HLA-II gene on the clinical characteristics of vitiligo in Chinese Han people.
Methods: using polymerase chain reaction (PCR) / sequence specific primers to explore the distribution of HLA-DRB1*07 alleles in 1178 patients with vitiligo and 1743 healthy controls, and to observe the differences in the clinical characteristics between the HLA-DRB1*07 allele positive vitiligo patients and the HLA-DRB1*07 negative patients.
Results: (1) the proportion of HLA-DRB1*07 positive in vitiligo cases was significantly higher than that in the control (40.75%vs.25.83%, OR:1.97,95%CI1.68-2.31, P=2.13 x 10-17). The frequency of DRB1*07 positive alleles in cases and controls was 0.20 and 0.13. in all cases of purpura wind, 480 cases were DRB1*07 diurnal. The 698 patients were DRB1*07 negative. In the case group, the average age of DRB1*07 diurnal patients was 25.57 + 14.45 years old, while the average age of DRB1*07 negative patients was 27.43 + 14.71 years (P=0.031). There was no significant difference between the male and female sex ratio in the DRB1*07 positive and negative two groups of vitiligo (P=0.099). (2) HLA-DRB1*07 positive vitiligo The median age of onset age of.HLA-DRB1*07 positive patients with vitiligo was 17 + 16 years older than that of DRB1*07 negative patients. The median of the onset age of HLA-DRB1*07 negative vitiligo patients was 19 + 18, and there was a significant difference between them (P=0.004). The frequency of early onset vitiligo in DRB1*07 positive patients It was also significantly higher in the negative patients (65.14%vs.55.59%, P=0.001, OR=1.49,95%CI1.17-1.90). (3) the incidence of family history of DRB1*07 positive vitiligo patients was higher than that of DRB1*07 negative patients. In the patients with DRB1*07 positive vitiligo, about 30.8% had family history, but only 23.6% of DRB1*07 negative patients had family history (OR=1.44.95%CI1). .11-1.87, P=0.006). (4) compared with DRB1*07 negative vitiligo patients, DRB1*07 positive patients had a higher frequency of autoimmune diseases (4.0%vs32%). However, the frequency difference between the two groups was not statistically significant (OR=1.27,95%CI0.68-2.37, P=0.458).
Conclusion: (1) there is a significant correlation between HLA-II gene and vitiligo in Chinese Han people. (2) there is a significant difference in the clinical characteristics of HLA-DRB1*07 positive patients with vitiligo in Chinese Han people and HLA*DRB1*07 negative patients. The incidence of disease in the patients with HLA-DRB1*07 positive vitiligo is earlier, and the incidence of family history is higher. (3) this study It is suggested that genetic factors related to autoimmune susceptibility may play an important role in the pathogenesis of some clinical features or subtypes of vitiligo.
【学位授予单位】：安徽医科大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R758.41

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