| 题名 | 中国都江堰汉族人群IIS信号通路基因的遗传变异与长寿的相关性研究 |
| 作者 | 谢亮 |
| 学位类别 | 博士 |
| 答辩日期 | 2009-06 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 张亚平 |
| 关键词 | 长寿 中国汉族 IIS信号通路 相关性研究 |
| 其他题名 | The Association Study of Genetic Variations in IIS Pathway Genes and Longevity in Dujiangyan Han Chinese Population |
| 中文摘要 | 随着人口老龄化的发展，对衰老和长寿的研究越来越受到关注。科学家们希望找到衰老相关疾病的致病机理以及治疗手段，从而降低这些疾病的发病风险，减少社会和经济负担。长寿老人受衰老相关疾病的困扰相对较少，自然成为研究的热点人群。而由于长寿的遗传力相对较高，关于长寿的遗传学研究也成为这个领域的热点之一。 作为在从无脊椎动物到脊椎动物中一条非常保守的信号通路，胰岛素/胰岛素样生长因子1（IIS）信号通路是一条与生长发育代谢密切相关的信号通路。同时，在模式生物的研究中发现，减弱这条信号通路会导致模式生物寿命的延长。而在人类群体的相关性研究中，这条通路上一些基因的遗传变异位点与长寿、血清胰岛素样生长因子1（IGF1）水平以及一些衰老相关疾病如糖尿病、癌症和心脑血管疾病相关。 为了探讨IIS信号通路上一些基因的遗传变异与长寿的关系，本研究在中国四川省都江堰市招募了共493名无相互关系的长寿老人，其中男性252人，年龄均大于90岁，女性241人，年龄均大于94岁。同时，在该地区招募了442名年轻的对照个体，年龄在22岁到73岁之间。我们对IIS信号通路上的一些基因的遗传变异位点利用测序，片段分析，RFLP等方法进行了扫描。包括（1）IGF1基因启动子区域及内含子1中的一个微卫星位点；（2）IGF1R基因外显子序列中的4个变异位点，包括3个SNP和一个2碱基缺失位点；（3）FOXO3A基因内含子1中的3个SNP位点。 本研究发现，在该人群中，IGF1基因启动子区域的遗传变异与长寿没有相关性，但携带该区域中的微卫星位点18/21基因型的男性个体在长寿群体中所占比例高于在对照群体中所占的比例(11.11 vs. 5.45%, p=0.011)。虽然经过多重检验校正后显著性消失了，但考虑到这个位点曾被报道与多种衰老相关疾病相关，因此，这个位点不是影响长寿的潜在功能位点，但有可能与真正的潜在功能位点相连锁，这一观点有待进一步研究的验证。本研究并没有发现IGF1R基因外显子序列中的遗传变异与长寿存在相关性。同时，研究结果支持FOXO3A基因的遗传变异与长寿相关，这样，继日籍美国人，德国人，意大利人群体后，在中国汉族人群中也证实了这一结果。同时，在FOXO3A基因上的一个未报道过的单核苷酸多态性（SNP）位点（109080595）在本研究中被发现，携带这个基因突变纯和基因型的个体仅在长寿人群中出现（8/492 vs. 0/414, 基因型分布差异p值为0.011）。关于FOXO3A基因的功能以及新发现位点在其他群体中的基因型分布情况值得进一步深入研究。 综上所述，本研究第一次在中国汉族人群中对IIS信号通路的一些基因的遗传变异与长寿的相关性进行了探讨，更多群体及更大样本量的研究有助于加深对长寿遗传机制的认识。 |
| 英文摘要 | With the worldwide increase of the aging population, more and more countries have to face the social and economic problems brought by the aging population. Scientists hope to elucidate the mechanisms of aging related diseases and find the treatment methods to them by focusing on aging and longevity researches. The ultimate aim is to decrease the risk of disease incidence and the social and economic burden. The longevity population, who succeed in escaping most of the aging related diseases, is an excellent model for aging and longevity researches and becomes a hotspot. On the other hand, the genetics of longevity gains more and more attentions for the relative high heritability of longevity. Insulin/IGF1 signaling pathway is a conserved pathway, which controls the growth and metabolism of organisms. In the researches on model animals, decreasing the signaling strength by mutation in the genes of this pathway can increase the life span of the animals. At the same time, in association studies in humans, scientists found that some genetic variations in the genes of this pathway are associated with serum IGF1 level, human longevity, and some aging related diseases such as diabetes, cancers and cardiovascular diseases. Therefore, we performed an association study in a Han Chinese population to quest the potential association between the genetic variations in genes of IIS pathway and longevity. In this study, 493 unrelated elderly individuals (age≥94 for female and age≥90 for male) were recruited from Dujiangyan in Sichuan province of China. Meanwhile, 442 control individuals, which were healthy local younger people, were recruited from the same area (age 22-73). We scanned the genetic variations in some genes of IIS pathway as follows: (1) the promoter region and a microsatellite site in intron 2 of IGF1 gene; (2) three SNPs and a 2bp deletion in exons of IGF1R gene; (3) three SNPs in intron1 of FOXO3A gene. Our results suggested that there are no associations between the genetic variations in IGF1 promoter region, intron 2 and IGF1R exons. However, there are more male individuals with 18/21 genotype of the microsatellite in IGF1 promoter region in longevity group than that in control group (11.11 vs. 5.45%, p=0.011). As the significance disappeared when corrected by Bonferroni’s method, considering that the microsatellite site was associated with many aging related diseases by many reports, we speculate that the 18/21 genotype can not be functional in longevity; however, it may link with the real functional site as there is a long haplotype block embracing the microsatellite locus. At the same time, our results confirmed that the genetic variations in FOXO3A gene were associated with longevity in a Han Chinese population, following the evidences in Japanese, Germany and Italian populations. Furthermore, we found a novel SNP in FOXO3A gene. The homozygotes of mutation allele of this SNP appear only in longevity groups (8/492 vs. 0/414, p=0.011). By our knowledge, it is the first time to report an association study of genetic variations in genes of IIS pathway and longevity. Future studies with more individuals in other populations will test our conclusions. |
| 语种 | 中文 |
| 公开日期 | 2010-10-22 |
| 内容类型 | 学位论文 |
| 源URL | [http://159.226.149.42:8088/handle/152453/6314]  |
| 专题 | 昆明动物研究所_分子进化基因组学 |
| 推荐引用方式 GB/T 7714 | 谢亮. 中国都江堰汉族人群IIS信号通路基因的遗传变异与长寿的相关性研究[D]. 北京. 中国科学院研究生院. 2009. |
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