A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon
A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon
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DOI：
10.1086/505915
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发表时间：
2006-09-01
影响因子：
9.8
通讯作者：
Stange, Eduard F.
中科院分区：
文献类型：
--
作者：
Fellermann, Klaus;Stange, Daniel E.;Stange, Eduard F.
防御素是内源性抗菌肽，可保护肠粘膜免受细菌侵袭。已经提出，不足的防御素表达可能是克罗恩病（CD）的慢性炎症的基础。 8p23.1染色体上的β-防御素基因簇的DNA拷贝数在健康人群中是高度多态性的，这表明结肠CD中的β-防fefensin诱导有缺陷可能是由于低β-防御素基因拷贝数低。在这里，我们通过基于阵列的比较基因组杂交和人类β-防御素2（HBD-2）基因的基于阵列的比较基因组杂交和定量聚合酶 - 链反应分析测试了这一假设。我们表明，健康个体以及溃疡性结肠炎患者的中位数为4（2-10）HBD -2基因拷贝每个基因组。在带回肠或结肠CD的手术队列中，在第二个大型队列中，炎症性肠疾病患者/肠切除/疾病的患者表现出正常的HBD-2拷贝数为4，而具有结肠CD的人则只有3份副本。每个基因组（对于手术队列；第二个队列的p = .008 p = .032）。总体而言，与对照组相比，结肠CD中的拷贝数分布转移到较低的数量（对于手术队列和与炎症性肠疾病的队列）。 P = .002 = 4份的个体（优势比3.06; 95％置信区间1.46-6.45）。 HBD-2基因拷贝数<4与粘膜HBD-2 mRNA表达降低有关（p = 0.033）。总之，β-防御素基因座中的HBD-2基因拷贝数较低，易于结肠CD，这很可能是通过β-防御素表达降低的。
Defensins are endogenous antimicrobial peptides that protect the intestinal mucosa against bacterial invasion. It has been suggested that deficient defensin expression may underlie the chronic inflammation of Crohn disease ( CD). The DNA copy number of the beta-defensin gene cluster on chromosome 8p23.1 is highly polymorphic within the healthy population, which suggests that the defective beta-defensin induction in colonic CD could be due to low beta-defensin gene copy number. Here, we tested this hypothesis, using genomewide DNA copy number profiling by array-based comparative genomic hybridization and quantitative polymerase-chain-reaction analysis of the human beta-defensin 2 (HBD-2) gene. We showed that healthy individuals, as well as patients with ulcerative colitis, have a median of 4 ( range 2 - 10) HBD-2 gene copies per genome. In a surgical cohort with ileal or colonic CD and in a second large cohort with inflammatory bowel diseases, those with ileal resections/disease exhibited a normal median HBD-2 copy number of 4, whereas those with colonic CD had a median of only 3 copies per genome ( for the surgical cohort; P = .008 P = .032 for the second cohort). Overall, the copy number distribution in colonic CD was shifted to lower numbers compared with controls ( for both the surgical cohort and the cohort with inflammatory bowel diseases). Individuals with P = .002 = 4 copies ( odds ratio 3.06; 95% confidence interval 1.46 - 6.45). An HBD-2 gene copy number of < 4 was associated with diminished mucosal HBD-2 mRNA expression (P = 0.033). In conclusion, a lower HBD-2 gene copy number in the beta-defensin locus predisposes to colonic CD, most likely through diminished beta-defensin expression.