HLA高分辨等位基因及单体型多态性与北方汉族髓系白血病的关联性研究  

Relationship between High-Resolution HLA-A,-B,-DRB1 Alleles and Haplotype Polymorphisms with Myeloid Leukemia of Han People in North China

作　　者：齐珺[1] 王天菊[1] 陈利萍[1] 王满妮[1] 武君华[1] 杜丹 

机构地区：[1]陕西省血液中心、中华骨髓库HLA高分辨分型确认实验室,陕西西安710061 [2]中国造血干细胞捐献者资料库管理中心,北京100013

出　　处：《中国实验血液学杂志》2018年第1期32-41,共10页Journal of Experimental Hematology

基　　金：中国造血干细胞捐献者资料库(CMDP)资助

摘　　要：目的:探讨HLA-A,-B,-DRB1高分辨等位基因及单体型多态性与北方汉族急性髓系白血病(AML)和慢性髓系白血病(CML)的相关性。方法:以1241例健康非亲缘造血干细胞捐献者为对照,采用PCR-SBT、-SSO和-SSP方法对259例髓系白血病患者进行HLA-A,B,DRB1高分辨分型,运用Arleguin 3.5.2软件计算基因频率及单体型频率,病例对照研究计算疾病比值比(ocld ratio,OR);用Swiss-Model对差异HLA分子进行同源建模,Swiss-Pdb Viewer v4.1软件对分子间三维结构进行差异比对。结果:经χ~2检验、连续校正显示,AML组(n=189)的A*02:07(8.47%vs 5.28%,P=0.013)、A*29:01(1.85%vs 0.68%,P=0.044)、B*07:02(5.29%vs 3.10%,P=0.029)、B*07:05:01G(1.85%vs 0.68%,P=0.044)、B*35:02(1.06%vs 0.20%,P=0.023)的基因频率高于对照组,而AML组的A*02:03频率则低于对照组(0.79%vs 3.10%,P=0.011)。CML组(n=70)的B*46:01频率低于对照组(2.86%vs 7.82%,P=0.031),但上述等位基因经Bonferroni校正后,均显示无统计学差异。经Fisher精确概率检验和Bonferroni校正,DRB1*11:28及其单体型A*24:02-B*15:01-DRB1*11:28频率在陕西籍CML患者中显著升高(1.43%vs 0.00%,Pc'=0.015;1.43%vs 0.00%,P=0.003)。Swiss-Pdb Viewer v 4.1软件计算DRB1*11:28和DRB1*11:01分子肽结合区主链间均方根偏差(RMSD)为0.09 nm。经Bonferroni校正单体型A*03:01-B*50:01-DRB1*07:01和A*11:01-B*40:06-DRB1*09:01分别在AML和CML患者中频率显著升高(1.06%vs 0.00%,Pc=0.000;2.86%vs 0.07%,Pc=0.000),与白血病呈正相关(OR=59.66,95%CI=3.21-1110.39;OR=42.91,95%CI=7.07-260.32)。结论:北方汉族AML和CML患者携带有特定的易感单体型,DRB1*11:28与CML发病呈正相关,可能不能有效结合并提呈bcr-abl肽段给CD4^+T细胞,是北方汉族尤其陕西籍发生CML的易感基因(OR=89.62,95%CI=4.28-1875.87),并与其特定单体型关联。Objective： To investigate the potential relationship between the high-resolution HLA-A,-B,-DRB1 alleles and haplotype polymorphism with actute myeloid leukemia（ AML） and chronic myeloid leukemia（ CML） of Han people in North China. Methods： A total of 1241 healthy unrelated Han people＇s bone marrowdonors in North China were used as a control group,259 patients with myeloid leukemia were genotyped at high-resolution level by means of PCR-SBT,-SSO and-SSP typing methods for HLA-A,-B,-DRB1 loci. The frequencies of HLA allele and haplotype were calculated by software Arleguin 3. 5. 2. The different distribution of genes and haplotypes was analyzed by case control study,and the odd ratio（ OR） of leukemia was also calculated. The structural difference of HLA alleles was analyzed 111 by HLA three-dimensional structure modeling and software Swiss-Pdb Viewer v4. 1. Results： χ^2 test and correction showed that an increased frequency of A＊ 02： 07（ 8. 47% vs 5. 28%,P＇ = 0. 013）,A ＊ 29： 01（ 1. 85% vs0. 68%,P = 0. 044）,B＊ 07： 02（ 5. 29% vs 3. 10%,P = 0. 029）,B＊ 07： 05： 01 G（ 1. 85% vs 0. 68%,P = 0. 044）and B＊ 35： 02（ 1. 06% vs 0. 20%,P = 0. 023） were found in AML patients（ n = 189） as compared with controls,respectively; whereas A＊ 02： 03 was less frequent in AML as compared with controls（ 0. 79% vs 3. 10%,P = 0. 011）.The frequency of B＊ 46： 01 was lower in CML patients（ n = 70） as compared with controls（ 2. 86% vs 7. 82%,P =0. 031）. However,the above-mentioned discrepancies were not statistically significant by Bonferroni correction.Through Fisher exact test and Bonferroni correction,the frequency of DRB1＊ 11： 28 and its haplotype A＊ 24： 02-B＊ 15：01-DRB1＊ 11： 28 in CML group were very significantly higher than in controls（ 1. 43% vs 0. 00%,Pc = 0. 015;1. 43% vs 0. 00%,P = 0. 003）. Three-dimensional structure modeling of DRB1 ＊ 11： 28 and DRB1 ＊ 11： 01 presented significant structure differentiation（ RMSD = 0.

关 键 词：髓系白血病 人类白细胞抗原 北方汉族 单体型 基因频率 比值比 HLA分子三维结构模拟 

分 类 号：R733.7[医药卫生—肿瘤]