A functional candidate screen for coeliac disease genes
A functional candidate screen for coeliac disease genes
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DOI：
10.1038/sj.ejhg.5201687
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发表时间：
2006-11-01
影响因子：
5.2
通讯作者：
Wijmenga, Cisca
中科院分区：
文献类型：
--
作者：
Curley, Christine R.;Monsuur, Alienke J.;Wijmenga, Cisca
越来越明显的是，不同的炎症性疾病在其病理特征、家族和个体的并发性以及共享的遗传因素方面显示出一些重叠。这可能也适用于乳糜泻，这是一种胃肠道系统的慢性炎症性疾病，与炎症性肠病共享两个连锁区域：染色体5 q31（CELIAC 2和IBD 5）和19 p13（CELIAC 4和IBD 6）。我们假设这些区域包含对这两种疾病易感的基因。重叠的5 q31区域仅包含5个位置候选基因，而重叠的19 p13区域包含141个基因。由于常见疾病基因可能在炎症中起作用，我们从19 p13区域中选择了五个功能候选基因。我们研究了这10个位置和功能的候选基因在我们的荷兰腹腔疾病队列使用44个单倍型标记单核苷酸多态性。来自19 p13的两个基因显示出对家族聚集的小影响：细胞色素P450 F3基因CYP 4F 3（P-标称0.0375，比值比（OR）1.77）和CYP 4F 2（P-标称0.013，OR 1.33）。CYP 4F 3和CYP 4F 2催化白三烯B4（LTB 4）的失活，LTB 4是一种负责中性粒细胞募集和活化的有效炎症介质。LTB 4调节基因变体的遗传关联将中性粒细胞动员的先天免疫应答与存在于乳糜泻患者中的已建立的Th 1适应性免疫应答相联系。腹腔疾病的发现需要复制。将这些细胞色素基因的遗传关联研究扩展到其他炎症性疾病，应该可以揭示它们的致病影响是否超出了乳糜泻。
It is increasingly evident that different inflammatory disorders show some overlap in their pathological features, concurrence in families and individuals, and shared genetic factors. This might also be true for coeliac disease, a chronic inflammatory disorder of the gastrointestinal system, which shares two linkage regions with inflammatory bowel disease: on chromosome 5q31 (CELIAC2 and IBD5) and 19p13 (CELIAC4 and IBD6). We hypothesised that these regions contain genes that contribute to susceptibility to both disorders. The overlapping 5q31 region contains only five positional candidate genes, whereas the overlapping 19p13 region has 141 genes. As the common disease gene probably plays a role in inflammation, we selected five functional candidate genes from the 19p13 region. We studied these 10 positional and functional candidate genes in our Dutch coeliac disease cohort using 44 haplotype tagging single-nucleotide polymorphisms. Two genes from 19p13 showed a small effect on familial clustering: the cytochrome P450 F3 gene CYP4F3 (P-nominal 0.0375, odds ratio (OR) 1.77) and CYP4F2 (P-nominal 0.013, OR 1.33). CYP4F3 and CYP4F2 catalyse the inactivation of leukotriene B4 (LTB4), a potent mediator of inflammation responsible for recruitment and activation of neutrophils. The genetic association of LTB4-regulating gene variants connects the innate immune response of neutrophil mobilisation with that of the established Th1 adaptive immunity present in coeliac disease patients. The findings in coeliac disease need to be replicated. Expanding genetic association studies of these cytochrome genes to other inflammatory conditions should reveal whether their causative influence extends beyond coeliac disease.