疾病易感性与基因多态性研究进展.ppt

主要内容 6 研究过程中遇到的实际问题有： Which genes which SNPs should we start with（从哪些基因哪些位点开始）? Polymorphisms of Low-penetrance genes: Why are the results always inconsistent? （为何相关性研究结果总是不一致？） How large the sample size is in molecular epidemiological studies (SNPs)? （样本量多大合适？） Which gene should we start with? Consideration of biology - Based on the mechanism of the disease(Biological plausibility, a definitive scientific hypothesis) Susceptive genes e.g. BRCA1, MSH2 Sensitive genes e.g. GSTM1, GSTT1 XRCC1, XPD CyclinD1, P53 Inconsistence of previous association studies of SNPs Low-penetrance genes Small sample size Publication bias Excessively emphasize the stratified results (without the main effect!) Limitations of observational studies Publication bias The selection from editor The abandon by researcher himself Too many subgroup results Large independent study with precise design Multi-center collaboration How big should the sample size be? How many genes and how many SNPs involved How high the frequency of polymorphisms How strong the association between polymorphisms and cancer Information from Meta-analysis e.g. NAT2 GSTM1 7 Strategies (I) Precise study design (pay attention to environmental exposures) Large sample size Multi-center collaboration High-throughput technology Strategies (II) Unpublished SNPs with functional evaluation Multi-sites within one gene Multi-genes in one pathway: the gene-gene interaction The combined analysis of genes involved in multi-pathway and multi-phase of the disease development Strategies (III) Analysis of haplotype and haplotype block Analysis of gene-environment interaction Analysis of genotype-phenotype correlation 多通路基因多态性与晚期结直肠癌对5-Fu化疗敏感性的关系 Stoehlmacher et al. British Journal of Cancer 2004 （5）基因芯片法：又称为DNA 微探针阵列（Micro array）。它集成了大量的密集排列的大量已知的序列探针，通过与被标记的若干靶核酸序列互补匹配，与芯片特定位点上的探针杂交，利用基因芯片杂交图象，确定杂交探针的位置，便可根据碱基互补匹配的原理确定靶基因的序列。这一技术已用于基因多态性的检测。对多态性和突变检测型基因芯片采用多色荧光探针杂交技术可以大大提高芯片的准确