HLA-DRB1基因多态性与肺结核易感性的病例对照研究

doi:10.3969/j.issn.1000-6621.2014.02.007

摘要/Abstract

摘要： 目的探讨HLA-DRB1基因多态性与唐山地区汉族人群肺结核发病的关系。方法采用1∶1配对的病例对照研究设计(2010年3—6月上旬在唐山市结核病医院）连续收治的汉族成人（年龄≥18岁）新发肺结核患者124例组成患者组；同时，再经统一结核菌素皮肤试验（TST）确认在同期为有结核分枝杆菌感染的健康体检者中，选择与患者组同民族、同性别、年龄相差不超过3岁、相同居住地匹配条件的共361名，且保证与每例患者匹配的对照至少有2名，在其中随机（扔硬币方法）选取1名与患者组患者结为对子，严格按照配对条件从361名中编号后随机抓取124名作为对照组。采用聚合酶链反应-特异性序列引物（PCR-SSP）和限制性片断长度多态性（PCR-RFLP）的方法检测HLA-DRB1基因DR15、DR16、DR1、DR11位点多态性，对与肺结核相关的危险因素进行问卷调查，应用SPSS 12.0软件进行单因素和多因素条件logistic回归分析。结果患者组中DR11野生型占85.5%（106/124），对照组野生型占87.1%（108/124），两组比较差异无统计学意义（P=0.712；OR=1.146；95%CI＝0.555~2.366）；患者组中DR16野生型占75.0%（93/124），对照组野生型占83.1%（103/124），两组比较差异无统计学意义（P=0.119；OR=1.635；95%CI＝0.879~3.042）；患者组中DR15野生型占85.3%（81/124），对照组野生型占82.2%（102/124），两组比较差异有统计学意义（P=0.002；OR=2.461；95%CI＝1.363~4.444）；故DR15基因突变型可能是肺结核发生的易感基因型；DR15位点突变如果与DR16位点突变同时存在时，风险增加（P=0.007；OR=4.904；95%CI=1.554~15.476），比单独的DR15、DR16位点突变的作用要大，说明该2个基因可能具有协同作用，能显著增加结核病的易感性。对17个环境危险因素进行了单因素条件logistic回归分析，在多因素分析中调整卡痕、体质指数、人均居住面积、家族史4个因素后，DR15突变基因型仍与肺结核显著相关（Waldχ²=9.844, P=0.002；OR=2.996；95%CI＝1.510～5.945）。结论 DR15基因突变型为结核病的易感基因型。

关键词: 结核, 肺/遗传学, HLA-DRB1链, 多态现象, 遗传, 疾病遗传易感性, 病例对照研究

Abstract: Objective To investigate the relationship between the HLA-DRB1 gene polymorphisms and susceptibility to pulmonary tuberculosis (PTB) in Han nationality of Tangshan city. Methods 1∶1 matched case-control study was adopted (in March to early June in 2010 in Tangshan TB hospitals), 124 new adult TB patients of Han nationality (age 18 and above) were enrolled consecutively as case group. Three hundred and sixty-one health people infected with Mycobacterium tuberculosis confirmed by the unified tuberculin test (PPD) in the physical examination, with the same nationality, same sex, similar age (age difference was less than 3 years), and same residence matching conditions, were selected at the same period. Each case had at least 2 people matched, in which 1 was randomly selected to match the case. One hundred and twenty-four people were randomly selected among 361 people as control group. Polymerase chain reaction-sequence-specific primers technique (PCR-SSP) and restriction fragment length polymorphism (RFLP) were used to type polymorphisms (DR15, DR16, DR1 and DR11). Information on environmental-related risk factors and pathological changes of TB was collected using a pre-tested standard questionnaire. Univariate and multivariate conditional logistic analysis were conducted using SPSS 12.0. Results DR11 wild type accounted for 85.5% (106/124) in case group and 87.1% (108/124) in control group, without statistical significance (P=0.712, OR=1.146, 95%CI＝0.555-2.366). Cases with DR16 wild type was 75.0% (93/124), and was 83.1% (103/124) in control group, there was no statistical significance (P=0.119, OR=1.635, 95%CI＝0.879-3.042)). Cases with DR15 wild type accounted for 85.3% (81/124), and 82.2% (102/124) in control group had this wild type, which was statistically lower than that in case group (P=0.002, OR=2.461, 95%CI＝1.363-4.444). According to the above results, DR15 gene mutation might be the susceptible genotype of PTB. If DR15 genetic mutation and DR16 genetic mutation occurred together, the risk of PTB increased (P=0.007, OR=4.904, 95%CI=1.554-15.476), which was significantly higher than any mutation, so that DR15 and DR16 has synergistic effects on PTB susceptibility. Univariate analysis was conducted for 17 environmental factors. In multivariate analysis, associations of TB and DR15 genotype still remained adjusting for scar of BCG, BMI, per capita living space and family history (Waldχ²=9.844,P=0.002, OR=2.996, 95%CI=1.510-5.945). Conclusion DR15 gene mutant might affect the susceptibility to TB in Han nationality in Tangshan city.

Key words: Tuberculosis, pulmonary/genetics, HLA-DRB1 chains, Polymorphism, genetic, Genetic predisposition to disease, Case-control studies

纪春梅，王育华，安雅臣，汪静，李林旭，张淑文. HLA-DRB1基因多态性与肺结核易感性的病例对照研究[J]. 中国防痨杂志, 2014, 36(2): 112-120. doi: 10.3969/j.issn.1000-6621.2014.02.007

JI Chun-mei, WANG Yu-hua, AN Ya-chen, WANG Jing, LI Lin-xu, ZHANG Shu-wen. A case-control study on the relationship between the HLA-DRB1 genetic polymorphisms and susceptibility to pulmonary tuberculosis[J]. Chinese Journal of Antituberculosis, 2014, 36(2): 112-120. doi: 10.3969/j.issn.1000-6621.2014.02.007

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