Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients
Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients
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DOI：
10.1016/j.crohns.2011.06.008
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发表时间：
2012-02-01
影响因子：
8
通讯作者：
De Hertogh, Gert
中科院分区：
文献类型：
--
作者：
Brinar, Marko;Vermeire, Severine;De Hertogh, Gert
背景和目的：肉芽肿是克罗恩病的特征性显微镜发现。它们的临床意义存在争议，其发病机制尚不清楚，但有人认为细菌成分的加工受损。自噬是消除细胞内细菌的基本过程。自噬基因 IRGM 和 ATG16L1 的遗传变异与克罗恩病的易感性有关。因此，我们研究了自噬基因的变异是否会导致肉芽肿的形成。方法：对来自 464 名临床记录充分的克罗恩病患者的手术标本进行检查，并对其肉芽肿的存在和分布进行评分。所有患者均对 ATG16L1 和 IRGM 中的 CD 相关 SNP 以及 13 个其他自噬基因中的 77 个单倍型标记 SNP 进行了基因分型。结果：75% 的患者发现肉芽肿。它们的频率随着胃肠道远端受累程度的增加而增加。肉芽肿阳性患者在诊断和手术时明显更年轻，并且更有可能吸烟。我们确定了肉芽肿与自噬基因变异 ATG4A (rs5973822)、FNBP1L (rs17109951) 和 ATG4D (rs7248026; rs2304165; rs10439163) 之间的关联。结论：这些发现表明肉芽肿形成是更具侵袭性的疾病过程的标志，并且自噬基因 ATG4A、 ATG2A、FNBP1L 和 ATG4D 可能有助于肉芽肿的形成。 (C) 2011 年欧洲克罗恩病和结肠炎组织。由 Elsevier B.V. 出版。保留所有权利。
Background and aims: Granulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn's disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation.Methods: Surgical specimens from 464 clinically well-documented Crohn's patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes.Results: Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163).Conclusion: These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation. (C) 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.