全基因组表达相关拷贝数变异在结直肠癌发生发展中的作用及机制研究

全基因组关联研究提示：显著影响"疾病相关基因"表达的遗传变异在易感性研究中容易"脱颖而出"，且有利于阐明疾病的生物学机制。拷贝数变异（Copy number variation，CNV），作为重要的影响DNA剂量的结构变异，对基因表达可产生重要影响。本研究前期利用HapMap的全基因组CNV数据及相应转录组数据，在全基因组范围内筛选出对基因表达影响最显著的CNV，并发现受这些CNV影响最显著的基因均为经典HLAⅡ类基因。鉴于HLAⅡ类基因在炎症所致肿瘤中的重要作用，本研究拟采用"两阶段病例-对照研究"策略，以严重危害我国居民健康的炎症相关肿瘤-结直肠癌为目标疾病，探索经典HLAⅡ类基因种系CNV在结直肠癌发生发展中的作用，并通过多种功能技术鉴定阳性关联CNV的功能。本研究为进一步探明HLAⅡ类基因遗传变异在结直肠癌发生发展中的作用提供新的线索，同时也为复杂性疾病遗传易感性研究提供了新思路。

Genome-wide association studies revealed outstanding positions and important roles in biological mechanism explanation of genetic variations that presented significant influence on the expression of disease-related genes. Copy number variation (CNV), as an important structural variation influencing DNA dosage, can exert impact on gene expression. Our study has screened out the CNVs that exert most significant influence on gene expression in whole genome based on CNV data from HapMap and related transcriptome data. Further investigations found that all genes regulated by above CNVs belonged to HLA class II genes. Given the important role of HLA class II genes in inflammation-related tumor and the significant public health impact of colorectal cancer as an inflammation-related tumor, a two stage case-control study will be carried out to detect the role of these CNVs of HLA class II genes in the initiation and development of colorectal cancer in Chinese Han population. Sequencing, FISH, Real-time PCR and Western blot will be further applied to detect the function of positive associated CNVs. Our study may not only provide novel evidence for the role of genetic variations in HLA class II genes in the initiation and development of colorectal cancer, but also present a new strategy to the study of complex disease susceptibility.