Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-α and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A
Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-α and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A
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DOI：
10.1111/j.1538-7836.2009.03636.x
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发表时间：
2009-12-01
影响因子：
10.4
通讯作者：
Oldenburg, J.
中科院分区：
文献类型：
--
作者：
Pavlova, A.;Delev, D.;Oldenburg, J.
背景：大约25%的重度血友病A（HA）患者产生因子VIII蛋白抗体。患者：在本病例对照队列研究中，对260例严重受累、突变型匹配的HA患者进行了人类白细胞抗原（HLA）II类分子与编码白细胞介素-10（IL-10）、肿瘤坏死因子-α（TNF-α）和细胞毒性T淋巴细胞抗原-4（CTLA-4）的基因多态性以及抑制剂产生的相关性研究。结果如下：我们的研究结果表明，DRB 1 *15和DQB 1 *0602等位基因以及单倍型DRB 1 *15/DQB 1 *0602在抑制剂患者中的频率较高[比值比（OR）1.9; P < 0.05]。在TNF-α中，-308G > A多态性的A等位基因在抑制剂队列中的频率较高（0.22 vs. 0.13，OR 1.80）。这一发现在纯合子A/A基因型中更为明显（OR 4.7）。对于IL-10，-1082G等位基因在抑制剂患者中更常见（0.55 vs. 0.43; P = 0.008）。根据遗传背景，首次确定了功能性细胞因子表型，这表明12%的抑制剂患者为高TNF-α/高IL-10产生者，而非抑制剂患者为3%（OR 4.4）。在抑制剂患者中发现CTLA-4中CT60多态性的A等位基因频率较低的趋势（0.42 vs. 0.50）。结论：总之，报告的数据清楚地强调了HLA分子在大型患者队列中参与抑制剂形成。在抑制剂患者中，TNF-α中-308G > A多态性和IL-10中-1082A > G多态性的频率较高，证实了早期发表的数据。CTLA-4中CT60单核苷酸多态性的重要性明显降低。
Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case-controlled cohort study, 260 severely affected, mutation-type-matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P < 0.05]. In TNF-alpha, the A allele of the -308G > A polymorphism was found with higher frequency in the inhibitor cohort (0.22 vs. 0.13, OR 1.80). This finding was more pronounced for the homozygous A/A genotype (OR 4.7). For IL-10, the -1082G allele was observed more frequently in patients with inhibitors (0.55 vs. 0.43; P = 0.008). The functional cytokine phenotype was determined for the first time, on the basis of the genetic background, and this showed that 12% of patients with inhibitors were high-TNF-alpha/high-IL-10 producers, as compared with 3% of non-inhibitor patients (OR 4.4). A trend for a lower frequency of the A allele of the CT60 polymorphism in CTLA-4 was found in inhibitor patients (0.42 vs. 0.50). Conclusions: In conclusion, the reported data clearly highlighted the participation of HLA molecules in inhibitor formation in a large cohort of patients. The higher frequencies of the -308G > A polymorphism in TNF-alpha and -1082A > G in IL-10 in inhibitor patients confirmed the earlier published data. The CT60 single-nucleotide polymorphism in CTLA-4 is of apparently less importance.