Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data
Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data
复制标题
DOI：
10.1093/carcin/bgu010
复制
发表时间：
2014-05-01
期刊：
影响因子：
4.7
通讯作者：
Li, Donghui
中科院分区：
文献类型：
--
作者：
Tang, Hongwei;Wei, Peng;Li, Donghui
我们在胰腺癌的GWAS数据中进行了基因吸烟交互作用分析。我们发现了轴突导向通路基因与吸烟在改变胰腺癌风险方面的可能相互作用。一旦得到证实，这将为揭示吸烟相关胰腺癌的病因开辟一条新的途径。吸烟是胰腺癌最好的可改变的危险因素。吸烟相关胰腺癌的遗传因素以前没有在全基因组水平上进行过研究。利用现有的全基因组关联研究（GWAS）的基因型和危险因素的数据从胰腺癌病例对照协会，我们进行了一项发现研究，在2028例和2109对照检查基因吸烟的相互作用在途径/基因/单核苷酸多态性（SNP）水平。使用似然比检验嵌套在逻辑回归模型和独创性通路分析（IPA），我们检查了172个KEGG（京都基因和基因组百科全书）通路，3个人工策划的基因集，3个尼古丁依赖基因本体通路，17 912个基因和468 114个SNP。调整多重比较后，没有一个单独的途径/基因/SNP与吸烟有显著的相互作用。6条KEGG通路与吸烟存在名义上的相互作用（P < 0.05），排在前2位的是胰腺分泌和唾液分泌通路（主要贡献基因：RAB 8A、PLCB和CTRB 1）。ZBED 2、EXO 1、PSG 2、SLC 36 A1、CLSTN 1、MTHFSD、FAT 2、IL 10 RB和ATXN 2等9个基因的P（互作）< 0.0005。EVC和KCNIP 4基因的5个基因间区SNP和2个SNP的P（交互作用）< 0.00003（.）在IPA分析与吸烟的名义相互作用的基因，轴突导向信号传导基因显着过度典型途径。对轴突引导信号传导通路有贡献的基因包括在胰腺癌中经常改变的SLIT/ROBO信号传导基因。这些观察结果需要在其他数据集中得到证实。一旦得到证实，它将为揭示吸烟相关胰腺癌的病因开辟一条新的途径。
We conducted gene-smoking interaction analysis in GWAS data of pancreati cancer. We found a possible interaction of axon guidance pathway genes with smoking in modifying the risk of pancreatic cancer. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genome-wide association study (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2028 cases and 2109 controls to examine gene-smoking interactions at pathway/gene/single nucleotide polymorphism (SNP) level. Using the likelihood ratio test nested in logistic regression models and ingenuity pathway analysis (IPA), we examined 172 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, 3 manually curated gene sets, 3 nicotine dependency gene ontology pathways, 17 912 genes and 468 114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P < 0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB and ATXN2 had P (interaction) < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had P (interaction) < 0.00003(.) In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional data set. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.