Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium.
Inflamm Bowel Dis. 2011 Jun;17(6):1392-7. doi: 10.1002/ibd.21486. Epub 2010 Nov 28.
The autophagy pathway has been linked with Crohn's disease (CD) through association of the ATG16L1 and IRGM genes with susceptibility for CD, and also to the Nod2 pathway, involved in CD. Our aim was to investigate polymorphisms in selected autophagy genes for their association with susceptibility to CD.
We prioritized all known human homologs of yeast autophagy (Atg) genes according to their location in a known inflammatory bowel disease (IBD) locus or in a genomic region detected in a genome-wide association study (GWAS) or GWAS-meta-analysis. A total of 70 haplotype tagging single nucleotide polymorphisms (tSNPs) in 12 genes were genotyped in a cohort of CD patients (n = 947) and controls (n = 548). Transmission disequilibrium testing (TDT) was performed in an independent cohort of 335 parent-child CD-trios.
The frequency of the T-allele of tSNP rs12303764 in ULK1 was significantly higher in CD (64%) versus controls (57%, corrected P-value 0.002). TDT demonstrated overtransmission of this allele to affected offspring (P = 0.02). Model-based multifactor dimensionality reduction (MB-MDR) interaction analysis confirmed a strong main effect for rs12303764. No interaction was found between ULK1 and CARD15, or between ULK1 genotypes and CD phenotypes.
We report a genetic association with a tSNP in ULK1, an interesting candidate gene for IBD, given the role of ULK1 in autophagy initiation, and the interaction between Nod2 and autophagy pathways. To further clarify the role of ULK1 in CD, an in-depth investigation of the variation in the region and possible role for copy number variation in this region should be evaluated.
自噬途径通过与克罗恩病（CD）易感性相关的 ATG16L1 和 IRGM 基因以及涉及 CD 的 Nod2 途径与 CD 相关。我们的目的是研究选定的自噬基因中的多态性与其对 CD 易感性的关联。
我们根据酵母自噬（Atg）基因在已知炎症性肠病（IBD）基因座中的位置或全基因组关联研究（GWAS）或 GWAS 荟萃分析中检测到的基因组区域，对所有已知人类同源物进行了优先级排序。在一组 CD 患者（n = 947）和对照组（n = 548）中，对 12 个基因中的 70 个单核苷酸多态性（SNP）进行了单体型标签单核苷酸多态性（tSNP）检测。在一个独立的 335 个 CD 亲子三联体的传递不平衡测试（TDT）中进行了测试。
在 CD（64%）与对照组（57%，校正后 P 值 0.002）相比，ULK1 中的 tSNP rs12303764 的 T 等位基因的频率明显更高。向受影响的后代传递此等位基因的 TDT 表明（P = 0.02）。基于模型的多因子维度缩减（MB-MDR）相互作用分析证实了 rs12303764 的主要作用。未发现 ULK1 与 CARD15 之间存在相互作用，或 ULK1 基因型与 CD 表型之间存在相互作用。
我们报告了与 ULK1 中的 tSNP 的遗传关联，这是一个有趣的 IBD 候选基因，因为 ULK1 在自噬起始中的作用以及 Nod2 和自噬途径之间的相互作用。为了进一步阐明 ULK1 在 CD 中的作用，应该评估该区域的变异和该区域可能存在的拷贝数变异的深入研究。
