Binder V, Orholm M
Herlev Hospital, University of Copenhagen, Denmark.
Neth J Med. 1996 Feb;48(2):53-6. doi: 10.1016/0300-2977(95)00093-3.
A number of studies have demonstrated aggregation of cases of ulcerative colitis or Crohn's disease in families, and of cases of both diseases within the same families, suggesting that patients share a genetic background. Perhaps because of differences in the selection of patients, study design and diagnostic criteria, different patterns of occurrence of inflammatory bowel disease (IBD) have been found among relatives of patients with these disorders. In recent years, however, several studies have been carried out, aiming by epidemiological methods to reveal (1) the frequency of familial occurrence of IBD among patients with ulcerative colitis and Crohn's disease, and (2) the prevalence of IBD among 1(0) relatives to patients with these diseases. Results from these studies show a relatively uniform pattern of family occurrence in about 10% of patients with ulcerative colitis and Crohn's disease, and a prevalence among 1(0) relatives of about 10 times that of the background population. A twin study reported a significantly higher concordance rate for Crohn's disease than for ulcerative colitis in monozygotic twins. By use of complex segregation analyses in 3 different studies, a very similar model of inheritance was found to fit for ulcerative colitis, namely a major dominant or additive gene with a low penetrance. For Crohn's disease the best-fitting model was a major recessive gene, with a high penetrance. This difference strongly supports the concept of ulcerative colitis and Crohn's disease as two separate disease entities. The occurrence of both diseases within the same families in certain members of the affected families is difficult to explain. The search for distinct associations of HLA genes with inflammatory bowel disease has shown a positive correlation between DR2 and ulcerative colitis and a negative association with DR4 and DRw6, compared with ethnically matched controls. In contrast, in Crohn's disease a positive association with the combination of DR1 and DQw5 alleles was revealed, thus indicating genetically different disease susceptibility for the two disorders. In general, however, no consistent pattern has been revealed from studies of association of HLA-A or -B antigens or blood group and serum protein markers. In two French families with several members affected with Crohn's disease no evidence for an HLA haplotype association could be revealed. Possible inherited markers of ulcerative colitis or Crohn's disease have been sought but without convincing success. Increased intestinal permeability, presence of anticolon antibodies and presence of antineutrophil leukocyte antibodies have been proposed, but not proved. Thorough studies are now needed of multimember families with disease for linkage studies to identify loci which contribute to increased liability. Such studies are in progress in different centres.
多项研究表明，溃疡性结肠炎或克罗恩病病例在家族中存在聚集现象，且同一家庭中这两种疾病的病例也有聚集，这表明患者具有共同的遗传背景。也许是由于患者选择、研究设计和诊断标准的差异，在这些疾病患者的亲属中发现了炎症性肠病（IBD）不同的发病模式。然而，近年来进行了几项研究，旨在通过流行病学方法揭示：（1）溃疡性结肠炎和克罗恩病患者中IBD家族发病的频率；（2）这些疾病患者的一级亲属中IBD的患病率。这些研究结果显示，在约10%的溃疡性结肠炎和克罗恩病患者中，家族发病模式相对一致，且一级亲属中的患病率约为背景人群的10倍。一项双胞胎研究报告称，单卵双胞胎中克罗恩病的一致性率显著高于溃疡性结肠炎。在3项不同研究中通过复杂分离分析发现，一种非常相似的遗传模式适用于溃疡性结肠炎，即一个主要的显性或加性基因，其外显率较低。对于克罗恩病，最适合的模式是一个主要的隐性基因，外显率较高。这种差异有力地支持了溃疡性结肠炎和克罗恩病是两个独立疾病实体的概念。在受影响家庭的某些成员中，同一家庭中出现这两种疾病的情况难以解释。对HLA基因与炎症性肠病的明显关联进行研究发现，与种族匹配的对照组相比，DR2与溃疡性结肠炎呈正相关，与DR4和DRw6呈负相关。相比之下，在克罗恩病中，发现与DR1和DQw5等位基因的组合呈正相关，从而表明这两种疾病在遗传易感性方面存在差异。然而总体而言，对HLA - A或 - B抗原、血型和血清蛋白标志物的关联研究未揭示出一致的模式。在两个有多名成员患克罗恩病的法国家庭中，未发现HLA单倍型关联的证据。人们一直在寻找溃疡性结肠炎或克罗恩病可能的遗传标志物，但未取得令人信服的成功。有人提出肠道通透性增加、抗结肠抗体的存在以及抗中性粒细胞白细胞抗体的存在，但均未得到证实。现在需要对患病的多成员家庭进行全面研究，以进行连锁研究来确定导致易感性增加的基因座。不同中心正在进行此类研究。
