Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation
Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation
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DOI：
10.1182/blood-2005-06-2338
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发表时间：
2006-03-01
期刊：
影响因子：
20.3
通讯作者：
Clark, JG
中科院分区：
文献类型：
--
作者：
Chien, JW;Zhao, LP;Clark, JG
先天性免疫参与移植物抗宿主病和常见呼吸道疾病的生物学研究。我们使用基于连锁不平衡的方法筛选了这一途径中的15个基因，以确定可能与造血细胞移植后气流障碍的发生有关的潜在候选基因。在一个发现队列中选择了69个单核苷酸多态进行评估(n=363)。重大关联在验证队列中得到验证(n=209)。通过检测基因转录本和蛋白在恶性和正常小气道上皮细胞中的表达，证实候选基因的表达。在发现队列中，133名患者出现了显著的气流下降。四种患者和供者的杀菌/通透性增加(BPI)单倍型与发生显著气流下降的风险增加2倍相关(P值，0.004-0.038)。这种关联在验证队列中得到了证实，该队列中有66名患者有显著的气流减少，有9种显著的单倍型(P值，0.013-0.043)。在呼吸道上皮细胞中检测到BPI基因转录本和蛋白。这些结果表明，BP/基因突变显著影响造血细胞移植后发生快速气流下降的风险，并可能代表这种形式的呼吸道疾病的新的治疗靶点。
Innate immunity is involved in the biology of graft versus host disease and common airway diseases. We screened 15 genes in this pathway using a linkage disequilibrium-based approach to identify potential candidate genes that may be involved in the development of airflow obstruction after hematopoietic cell transplantation. Sixty-nine single-nucleotide polymorphisms were selected for assessment in a discovery cohort (n = 363). Significant associations were validated in a validation cohort (n = 209). Expression of the candidate gene was demonstrated by detecting gene transcript and protein in malignant and normal small airway epithelial cells. In the discovery cohort, 133 patients developed significant airflow decline. Four patient and donor bactericidal/permeability-increasing (BPI) haplotypes were associated with a 2-fold to Vold increased risk of developing significant airflow decline (P values, .004-.038). This association was confirmed in the validation cohort, which had 66 patients with significant airflow decline, with 9 significant haplotypes (P values, .013-.043). BPI gene transcript and protein were detected in airway epithelial cells. These results suggest mutations in the BP/gene significantly influence the risk of developing rapid airflow decline after hematopoietic cell transplantation and may represent a novel therapeutic target for this form of airway disease.