Recent insights into the genetics of inflammatory bowel disease.
Recent insights into the genetics of inflammatory bowel disease.
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DOI：
10.1053/j.gastro.2011.02.046
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发表时间：
2011-05
期刊：
影响因子：
29.4
通讯作者：
Brant SR
中科院分区：
文献类型：
--
作者：
Cho JH;Brant SR
炎症性肠病（IBD）是一种复杂的多因素疾病，包括克罗恩病（CD）和溃疡性结肠炎（UC）。全基因组关联研究已经确定了大约100个与IBD显著相关的基因座。这些基因座涉及多种基因和病理生理机制，包括微生物识别、淋巴细胞活化、细胞因子信号传导和肠上皮防御。与流行病学预测一致，许多IBD相关基因座显示出与CD和UC的全基因组显著相关性，特别是其产物在白细胞介素-2-3途径中起作用的基因，以及转录因子，包括NK 2转录因子相关基因座3（NKX 2 -3）、SMAD 3、STAT 3、ZMIZ 1和c-REL。虽然CD和UC都与涉及白细胞运输的基因产物的基因组区域相关，但有证据表明CD和UC之间的关联模式不同。CD主导的协会包括NOD 2和调节自噬的基因。在UC中，主要的关联信号位于染色体6p 21上，在主要组织相容性复合体区域，靠近HLA II类基因。UC占优势的基因座也涉及介导上皮防御功能的基因。疾病之间存在显著的基因座重叠，这可以提供对疾病发病机制的比较洞察。编码在白细胞介素-23通路中起作用的因子的基因与许多慢性炎性疾病相关，特别是银屑病和强直性脊柱炎。不同的遗传相关性表明，与原发性硬化性胆管炎相关的结肠炎在病理生理学上不同于与原发性硬化性胆管炎无关的UC。IBD和乳糜泻之间共有多达14个易感基因座，表明病理生理学有显著重叠。未来的遗传学研究将致力于识别具有潜在更大统计学效应的不常见变异，确定人群差异，并更全面地解释疾病的家族传播。
Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemio-logic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and anky-losing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying un common variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease.