人类白细胞抗原-DRB1基因多态性与山西省家族性乙型肝炎预后的相关性研究

Human leukocyte antigen-DRB1 polymorphism is associated with the outcome of familial hepatitis B in Shanxi Province

目的探讨人类白细胞抗原（human lymphoeyte antigen，HLA）-DRB1等位基因多态性与山西省家族性乙型肝炎临床转归及乙型肝炎病毒（HBV）复制状态的相关性。方法采用前瞻性临床流行病学研究方法，以山西省家族性乙型肝炎家庭中的295位成员为研究对象，将其分为健康对照组、慢性无症状携带（ASC）组、慢性乙型肝炎（CHB）组及肝硬化组。采用聚合酶链反应．序列特异性寡核苷酸探针技术（polymerase chain reaction—sequence specific oligonucleotide probe，PCR—SSOP）结合荧光磁珠流式检测技术，进行HLA—DRB1等位基因检测。采用，检验或Fisher’s确切概率计算法比较HLA—DRB1各等位基因频率在各组间以及在HBV DNA不同载量下的分布情况，组间计量资料比较采用方差分析，相关疾病的等位基因风险率以相对危险系数（RR）表示。结果HLA—DRB＊04基因频率在健康对照组为0．159，明显高于ASC组（0．069）和CHB组（0．079），差异具有统计学意义（χ^2分别为4．892和4．072，P值均〈0．05）；HLA—DRB1＊07等位基因在CHB组和肝硬化组的频率分别为0．131和0．154，明显高于健康对照组（0．049），差异具有统计学意义（χ^2值分别为4．140和5．529，P值均〈0．05）；HLA—DRB1＊13等位基因频率在健康对照组为0．037，高于CHB组（0），2组比较差异具有统计学意义（χ^2=3．316，P〈0．05）。HLA—DRB1＊15等位基因频率在ASC组为0．206，在肝硬化组为0．115，2组比较差异具有统计学意义（χ^2=4．287，P〈0．05）。其他各等位基因频率在各组间差异无统计学意义。患者年龄在ASC、CHB及肝硬化3组间的差异有统计学意义（F=33．38，P〈0．01）；HBV DNA阳性组的HLA—DRB1＊07基因频率（0．167）高于HBV DNA阴性组（0．096）（χ^2=5．268，P=0．002）。结论HLA—DRB1＊07与家族性HBV易感性有关，可能是山西省家族性乙型肝炎易感基因或连锁基因。HLA—DRBI＊04及HLA—DRB1＊13与家族性乙型肝炎抗性相关，可能是山西省家族性乙型肝炎抗性基因。

Objective To assess the associations of human leukocyte antigen （HLA）-DRB1 polymorphism with the outcome of familial hepatitis B and the replication of hepatitis B virus （ HBV ） in Shanxi province. Methods A prospective clinical and epidemiological study was performed in 295 subjects from hepatitis B families who were divided into the healthy control group, chronic asymptomatic carrier （ASC） group, chronic hepatitis B （CHB） group and liver eirrhosis group. The frequencies of HLA-DRB1 were deteeted by polymerase chain reaction-sequence specific oligonucleotide probe （PCR-SSOP） and fluorescence luminex flow technique. χ^2 test and Fisher＇s exact probability test were used to compare the frequencies of HLA-DRB1 among the groups and among different replications of HBV. Analysis of variance was performed to compare the measurement data among groups. The relative risks for HLA-DRB1 associated with other diseases were expressed in HR. Results The frequency of HLA-DRB1 ＊ 04 in the healthy control was 0. 159, which was higher than those in CHB group （0. 069） and liver cirrhosis group （0. 079）, and the differences were of statistical significance （χ^2 = 4. 892 and 4. 072, P 〈 0. 05 ）. The frequencies of HLA- DRB1 ＊ 07 in CHB group and liver cirrhosis group were 0. 131 and 0. 154, significantly higher than that in the healthy control （0.049, χ^2 =4. 140 and 5. 529, P 〈0.05）. The frequency of HLA-DRB1 ＊ 13 in the healthy control group was 0. 037, which was higher than that in the CHB group （0, χ^2 = 3. 316, P 〈 0.05）. The frequencies of HLA-DRB1 ＊ 15 in ASC group and liver cirrhosis group were 0. 206 and 0. 115, the difference between the two groups was of statistical significance （χ^2 = 4.287, P 〈 0.05 ）. The frequencies of other DRB1 alleles were not significantly different among the groups. Significant difference on the average ages was observed among ASC, CHB and liver cirrhosis groups （F = 33.38, P 〈 0.01 ）. The frequency of HLA- DRB1 ＊ 07 was significantly higher in the HBV DNA positive group than that in the HBV DNA negative group （0. 167 vs. 0. 096, χ^2 = 5. 268, P = 0. 002）. Conclusions HLA-DRB1 ＊ 07 allele is associated with the susceptibility to familial hepatitis B, which may be the susceptibility gene or linked gene for familial hepatitis B in Shanxi province. HLA-DRB1 ＊ 04 and HLA-DRB1 ＊ 13 are associated with the resistance to familial hepatitis B, which may be the resistant genes for familial hepatitis B in Shanxi province.