南方汉族KIR-HLA系统基因多态性与慢性髓系白血病的相关性

摘要

目的 探讨中国南方汉族人群KIR-HLA系统基因多态性与慢性髓系白血病(chronic myeloid leukemia,CML)的相关性.方法 对172份成年CML患者及480份随机正常对照的样本,采用PCR-SSP方法检测KIR基因,用测序分型法进行HLA-A、-B、-C基因分型.从KIR基因及其基因组合型、HLA Ⅰ类配体、已知的单个KIR+ HLA受-配体组合及KIR-HLA基因型组合等4个层次比较病例组与对照组分子遗传多态性的差异.结果 与KIR2DL1配位的HLA-C2、KIR2DL1+ HLA-C2、与KIR3DL1配位的HLA-B Bw4-80I的检出频率均显著低于正常对照组,为CML保护因素(HLA-C2:OR=0.386,95％CI:0.240～0.620,P＜0.01;KIR2DL1-+ HLA-C2:OR=0.316,95％CI:0.191～0.525,P＜0.01;HLA-B Bw4-80I:OR=0.576,95％CI:0.384～0.862,P＜0.01).HLA-C2及HLA-B Bw4-80I分子表达机率降低,可能导致与相应的抑制性KIR亲和力的减弱,有利于NK细胞活化.最值得注意的是:KIR-HLA基因型组合ID2(KIR AA1-HLA-C1/C1-Bw6/Bw6-A3/11)在CML组的检出频率显著高于正常对照组,为CML易感因素(OR=2.163,95％CI:1.198～3.906,P＜0.01).结论 本研究识别了KIR-HLA与CML白血病相关的易感或保护性因素,可为CML白血病的发病机制和个体化免疫治疗提供新的线索及理论依据.%Objective To explore the association of KIR-HLA gene polymorphism with chronic myeloid leukemia (CML) among ethnic Hans from southern China.Methods A total of 172 adult CML patients and 480 unrelated healthy controls were screened for the presence of KIR with sequence-specific primers-PCR (PCR-SSP) and sequence-based typing (SBT) of HLA-A,-B and-C loci.Polymorphisms of the KIR-HLA system were analyzed at 4 levels,and the frequencies of KIR framework genes and KIR profiles,class Ⅰ HLA ligands,matched KIR+ HLA pairs and KIR-HLA compound profile were compared between the two groups.P values were calculated using SPSS 13.0 software.Results For the CML group,the frequencies of HLA-C2 ligand,2DL1+-HLA-C2 pair and HLA-B Bw4-80I were significantly lower than those of the control group,suggesting a protective effect against CML (HLA-C2:OR =0.386,95 ％ CI:0.240-0.620,P＜0.01;2DL1+HLA-C2:OR=0.316,95％CI:0.191-0.525,P＜0.01;HLA-B Bw4-80I:OR=0.576,95％CI:0.384-0.862,P＜0.01).The frequencies of KIR2DL1 ligand (HLA-C2) and KIR3DL1 ligand (HLA-B Bw4-80I) in the CML group were significantly lower than that of the control group,suggesting that the HLA-C2 and HLA-B Bw4-80I expression is probably decreased in the CML patient group,which led to reduced inhibitory signal and enhanced activating signal of KIR2DL1+ and/or KIR3DL1+ NK cells.Notably,the frequency of KIR-HLA compound profiles ID2 (KIR AA1-HLA-C1/C1-Bw6/Bw6-A3/11) in CML patients significantly increased in the CML patient group compared with the control group,suggesting that the KIR-HLA compound profiles ID2 may be a risk factor for CML (OR=2.163,95％CI 1.198-3.906,P＜0.01).Conclusion Above analysis has identified certain protective and risk factors for CML from the KIR-HLA system,which may provide a clue for the pathogenesis of leukemia and development of individualized immune therapy.