Fellermann Klaus, Stange Daniel E, Schaeffeler Elke, Schmalzl Hartmut, Wehkamp Jan, Bevins Charles L, Reinisch Walter, Teml Alexander, Schwab Matthias, Lichter Peter, Radlwimmer Bernhard, Stange Eduard F
Department of Internal Medicine I, Robert-Bosch-Hospital, 70376 Stuttgart, Germany.
Am J Hum Genet. 2006 Sep;79(3):439-48. doi: 10.1086/505915. Epub 2006 Jul 12.
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 (P=.008 for the surgical cohort; P=.032 for the second cohort). Overall, the copy number distribution in colonic CD was shifted to lower numbers compared with controls (P=.002 for both the surgical cohort and the cohort with inflammatory bowel diseases). Individuals with < or = 3 copies have a significantly higher risk of developing colonic CD than did individuals with > or = 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=.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.
防御素是内源性抗菌肽，可保护肠道黏膜免受细菌侵袭。有人提出，防御素表达不足可能是克罗恩病（CD）慢性炎症的基础。8号染色体p23.1上β-防御素基因簇的DNA拷贝数在健康人群中具有高度多态性，这表明结肠CD中β-防御素诱导缺陷可能是由于β-防御素基因拷贝数低所致。在此，我们通过基于阵列的比较基因组杂交进行全基因组DNA拷贝数分析以及对人β-防御素2（HBD-2）基因进行定量聚合酶链反应分析来验证这一假设。我们发现，健康个体以及溃疡性结肠炎患者每个基因组中HBD-2基因拷贝数的中位数为4（范围为2至10）。在一个患有回肠或结肠CD的手术队列以及另一个患有炎症性肠病的大型队列中，接受回肠切除/患有回肠疾病的患者HBD-2拷贝数中位数正常，为4，而患有结肠CD的患者每个基因组中HBD-2拷贝数中位数仅为3（手术队列中P = 0.008；第二个队列中P = 0.032）。总体而言，与对照组相比，结肠CD中的拷贝数分布向较低数值偏移（手术队列和炎症性肠病队列中P均为0.002）。拷贝数≤3的个体患结肠CD的风险显著高于拷贝数≥4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与黏膜HBD-2 mRNA表达降低相关（P = 0.033）。总之，β-防御素基因座中较低的HBD-2基因拷贝数易导致结肠CD，很可能是通过降低β-防御素表达实现的。
