人类白细胞抗原高分辨等位基因及单倍型与北方汉族急性淋巴细胞白血病的关联性

Association of HLA-A,-B,-DRB1 alleles and hapiotypes with acute lymphoblastic leukemia among ethnic Hans from northern China

目的探讨人类白细胞抗原（human leukocyte antigen，HLA）-A，-B，-DRB1高分辨等位基因及单倍型多态性与北方汉族急性淋巴细胞白血病（acutelymphoblastic leukemia，ALL）的相关性。方法以1241名正常非亲缘造血干细胞捐献者为对照，应用聚合酶链反应一测序分型（polymerase chain reaction-sequence-basedtyping，PCR-SBT）、序列特异寡核苷酸探针技术（sequence specific oligonucleotide probes，SSO）和组特异性引物扩增（sequence specificprimer，SSP）方法对170例ALL患者进行HLA-A、-B、-DRB1高分辨分型，用Arlequin3．5．2软件计算HLA基因频率和单倍型频率，计算疾病比值比（oddratio，OR）进行病例对照研究。结果经X2检验、连续校正显示，与对照组相比ALL患者的B＊13：01和B＊40：02频率升高（7．35％弧4．63％，P=0．030；2．94％vs．1．45％，P=0．042），而B＊35：03和B＊46：01频率降低（O．29％强1．69％，P=0．048；4．41％7iS．7．82％，P=0．025），但经Bonferroni校正后显示差异均无统计学意义。在ALL患者中频率增加的DRB1＊15组尽管经Bonferroni校正后差异无统计学意义，但其组内的DRB1＊15：01基因频率经Bonferroni校正后仍显著高于对照组（16．18％邯．10．19％，Pc’=0．041），与ALL呈正相关（OR=1．70，95％CI：1．24～2．33）。19种单倍型在ALL中的频率显著高于对照组，其中11种单倍型在对照组中未出现过，与白血病呈正相关。结论本研究获得了HLAA、-B、-DRB1高分辨等位基因及单倍型与北方汉族ALL相关性的资料，DRB1＊15：01与北方汉族ALL患者正相关，可能是北方汉族发生ALL的易感基因，并与其特定单倍型关联。

[Abstract] Objective To assess the association of polymorphisms of human leukocyte antigen （HLA）-A,-B,-DRB1 alleles and haplotypes with acute lymphoblastic leukemia （ALL） among ethnic Hans from northern China. Methods A total of 170 ALL patients （patient group） and 1241 unrelated healthy bone marrow donors （control group） were genotyped at a high-resolution level using polymerase chain reaction-sequence-based typing （PCR-SBT）, sequence specific oligonucleotide probes （SSO） and sequence specific primer （SSP） typing methods. Frequencies of HLA alleles and haplotypes were calculated with Arlequin 3. 5.2 software. The distribution of genes and haplotypes were analyzed through a case-control study, and the odd ratio （OR） of ALL was also calculated. Results By ;（2 test and correction, an increased frequency of B ＊ 13：01 and B ＊ 40102 among ALL patients was discovered in comparison with the controls （7.35% vs. 4.63%, P=0.030;2.94% vs. 1.45%, P=0.042）, whereas B＊ 35..03 and B＊ 46..01 were less frequent compared with the controls （0.29% vs. 1.69%, P=0. 048; 4.41% vs. 7.82~, P=0. 025）. Although the above discrepancies were not statistically significant by Bonferroni correction, within DRB1 15 group, the frequency of DRB1 ＊ 15：01 in ALL patients was significantly greater than that of the controls （16.18% vs. 10. 19%, Pc＇=0.041） and was correlated with ALL （OR=1. 70, 95%CI：1.24-2. 33）.Nineteen haplotypes identified in the ALL patients had a frequency greater than those of the controls. Of these, 11 were absent from the control group and were correlated with ALL. Conclusion The association of HLA-A,-B,-DRB1 polymorphisms with ALL was determined among patients from northern Chinese Hans. The correlation between DRB1 ＊＊ 15：01 and ALL suggested that DRB1 ＊ 15：01 may be a susceptibility gene for ALL with its particular haplotylaes.