【摘 要】
：
目的 全基因组关联研究(GWAS)揭示ATG16L1是CD的易感基因,而ATG12-ATG5-ATG16L1共轭复合体是自噬信号通路中一个关键性节点.本研究进一步深入探讨ATG12和ATG5是否与CD发病相关,以及3个自噬体基因是否具有协同作用.方法 除已报道的ATG16L1中的rs2241880外,在ATG5和ATG12中挑选出9个和4个尚未被纳入GWAS研究的潜在的标记单核苷酸多态性(SNP)
【机 构】
：
成都,四川大学华西医院消化内科;英国剑桥大学Addenbrooke医院消化内科 MRC公共卫生研究
【出 处】
：
The 14th Congress of Gastroenterology China(第十四届全国消化系病学术会议)
论文部分内容阅读
目的 全基因组关联研究(GWAS)揭示ATG16L1是CD的易感基因,而ATG12-ATG5-ATG16L1共轭复合体是自噬信号通路中一个关键性节点.本研究进一步深入探讨ATG12和ATG5是否与CD发病相关,以及3个自噬体基因是否具有协同作用.方法 除已报道的ATG16L1中的rs2241880外,在ATG5和ATG12中挑选出9个和4个尚未被纳入GWAS研究的潜在的标记单核苷酸多态性(SNP)供外周血DNA基因分型.首先在样本组1(704个CD和1056个对照黏膜)中对14个SNP基因分型,所得CD相关SNP进一步在样本组2中分型(566个CD和264个对照黏膜).在正常组3(97个对照末回黏膜)中进行所得CD相关SNP基因型和相应自噬基因表达分型相关性分析.进一步在检测3个基因在病例组4(24个缓解期CD和22个活动期CD末回黏膜)中的表达.结果 基因分型结果经x2检验发现,在样本组1中rs2241880与CD强烈相关(P=0.000),而ATG5中无单个SNP与CD相关,而ATG12中rs26534(P=0.017)和rs26538(P=0.014)与CD相关.样本组2的基因分型结果发现,3个SNP仍与CD相关,其中ATG12中的两个SNP相关性进一步增强(P值分别为0.0167和0.0025).对3个SNP的碱基和基因型水平的似然比逻辑回归分析发现,即使rs2241880已经充分证实与CD易感性相关,但是当其与余下两个SNP组合分析时,其相关性更强,表明ATG12和ATG16L1可能协同促进CD的易感性.正常组3中基因表达qPCR发现,ATG12与ATG16L1表达与其相应SNP的基因型均不相关.结合病例组4中基因表达研究发现,CD活动期、非活动期和正常对照组的ATG5和ATG16L1表达的差异均有统计学意义(P值分别=0.001 2、0.000 3).而ATG12表达的差异无统计学意义.若排除炎性反应和药物等影响,正常对照中3个基因表达均两两相关((r值为＜0.65～＜0.71).结论 新发现ATG12中2个SNP与CD易感性相关.SNP易感性非通过影响基因表达水平来实现.共轭复合体ATG12-ATG5-ATG16L13个基因在CD的发病机制中起协同作用,但具体的详细机制需进一步深入研究.
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