Genetica Medica, Dipartimento di Scienze Biomediche, Università degli Studi di Foggia, Foggia, Italy.
Haemophilia. 2010 May;16(3):469-73. doi: 10.1111/j.1365-2516.2009.02150.x. Epub 2009 Dec 14.
One of the most severe and important complication in the treatment of patients with haemophilia A is the formation of neutralizing antibodies (FVIII inhibitors) that inhibit the clotting activity of substituted FVIII. Both genetic and environmental factors influence the susceptibility of patients to develop inhibitors. The objective of this study was to evaluate whether polymorphisms in different genes involved in the regulation of the immune system may confer susceptibility to inhibitor development in patients with HA. We analysed the distribution of polymorphisms in the CTLA4, PTPN22, IL10, TNFalpha, FOXP3 and IRF5 genes that have been reported to be associated with a number of autoimmune disease. In addition, we evaluated the distribution of IL10 haplotypes in haemophilic patients and healthy controls to assess whether specific polymorphisms in IL10 gene were associated to the risk of inhibitor development. We focused on a cohort of Italian unrelated haemophilic patients with and without a history of inhibitors. Genotyping was carried out with standard methods including RFLP, real time PCR and direct DNA sequencing. Our data show that, considering single nucleotide variations, genotype frequencies in patients with inhibitors were not significantly different from those observed in patients without inhibitors, suggesting a lack of association between these polymorphisms and the development of inhibitors. Moreover, no relationship was found between specific combinations of IL10 alleles and the antibody production. Previous contradictory association studies may depend on the different genetic background of the population examined. Further studies may contribute to a clearer understanding of this process.
在治疗甲型血友病患者的过程中，最严重和最重要的并发症之一是产生中和抗体（FVIII 抑制剂），这种抗体抑制替代 FVIII 的凝血活性。遗传和环境因素都会影响患者产生抑制剂的易感性。本研究的目的是评估免疫系统调节相关的不同基因中的多态性是否可能使血友病 A 患者易发生抑制剂的产生。我们分析了 CTLA4、PTPN22、IL10、TNFalpha、FOXP3 和 IRF5 等基因中的多态性分布，这些基因已被报道与许多自身免疫性疾病有关。此外，我们评估了血友病患者和健康对照者中 IL10 单倍型的分布，以评估 IL10 基因中特定的多态性是否与抑制剂发展的风险相关。我们专注于一组意大利无关的血友病患者，他们有或没有抑制剂的历史。采用包括 RFLP、实时 PCR 和直接 DNA 测序在内的标准方法进行基因分型。我们的数据表明，考虑到单核苷酸变异，抑制剂患者的基因型频率与无抑制剂患者观察到的频率没有显著差异，这表明这些多态性与抑制剂的发展之间缺乏关联。此外，IL10 等位基因的特定组合与抗体产生之间也没有关系。以前的关联研究可能取决于所检查人群的不同遗传背景。进一步的研究可能有助于更清楚地了解这一过程。
