Duerr Richard H
School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
J Clin Gastroenterol. 2003 Nov-Dec;37(5):358-67. doi: 10.1097/00004836-200311000-00003.
There is a general consensus that interplay of genetic and environmental factors leads to an overactive mucosal immune response, which mediates the tissue damage in inflammatory bowel disease. Ethnic aggregation of inflammatory bowel disease (particularly, increased incidence and prevalence in the Ashkenazim), familial aggregation of inflammatory bowel disease, and greater concordance for inflammatory bowel disease in monozygotic twins than dizygotic twins are 3 lines of evidence for a central role of genetic factors in the pathogenesis. The genetics of inflammatory bowel disease cannot be explained by simple Mendelian genetics; it is characterized by incomplete penetrance, multiple susceptibility loci and genetic heterogeneity. Unraveling the complex genetics of inflammatory bowel disease is a daunting challenge, but the perseverance of inflammatory bowel disease gene hunters has produced commendable results in recent years. Since 1996, the field of inflammatory bowel disease genetics has progressed from publication of the first systematic genome searches for inflammatory bowel disease susceptibility loci to the identification of Crohn disease-associated genetic variants in CARD15/NOD2. Strategies for finding additional inflammatory bowel disease genes include taking advantage of the greater resolution and power of linkage disequilibrium mapping, mapping by admixture disequilibrium in African-American and Hispanic-American populations, stratifying genetic analyses by genotypes at known inflammatory bowel disease loci, and refining inflammatory bowel disease phenotypes to reduce genetic heterogeneity and simplify the search for additional inflammatory bowel disease genes.
人们普遍认为，遗传因素和环境因素的相互作用会导致黏膜免疫反应过度活跃，进而介导炎症性肠病中的组织损伤。炎症性肠病的种族聚集现象（尤其是阿什肯纳兹犹太人的发病率和患病率增加）、炎症性肠病的家族聚集现象，以及同卵双胞胎比异卵双胞胎患炎症性肠病的一致性更高，这三条证据表明遗传因素在发病机制中起核心作用。炎症性肠病的遗传学不能用简单的孟德尔遗传学来解释；其特点是外显率不完全、多个易感基因座和遗传异质性。解开炎症性肠病复杂的遗传学是一项艰巨的挑战，但近年来炎症性肠病基因研究者的坚持不懈取得了值得称赞的成果。自1996年以来，炎症性肠病遗传学领域已从首次系统性地搜索炎症性肠病易感基因座的基因组研究发展到在CARD15/NOD2中鉴定克罗恩病相关的基因变异。寻找其他炎症性肠病基因的策略包括利用连锁不平衡图谱更高的分辨率和效力、在非裔美国人和西班牙裔美国人中通过混合不平衡进行图谱绘制、根据已知炎症性肠病基因座的基因型对遗传分析进行分层，以及细化炎症性肠病表型以减少遗传异质性并简化寻找其他炎症性肠病基因的工作。
