[医学]北大田小利小组等发现两个与长寿相关基因

dr.qinan

北京大学分子医学研究所人类群体遗传研究室田小利教授与国家发展研究院中国经济研究中心曾毅教授联合研究组发现FOXO1A和FOXO3A基因与长寿相关。他们的研究表明FOXO1A与我国女性的长寿相关，而FOXO3A基因则没有性别差异。该研究结果发表于经典遗传学杂志《人类分子遗传学》（Human Molecular Genetics）。

健康长寿是每一个人的梦想，但影响健康长寿的因素很多，包括性别、遗传、生活习惯和生活环境及其相互作用等。在年龄大于85岁的人群中女性约占70-85%，而男性仅为15-30%。尽管女性的长寿优势可见于已经报道的所有人种，但原因尚不明确。田小利教授研究组首次发现FOXO1A基因与女性的长寿相关，将有助于解释女性长寿之谜。FOXO3A基因曾报道与其他的人群（如日本人、德国人和意大利人等）的长寿相关。中国人FOXO3A基因的长寿位点与其他人群的长寿位点共存于一个单倍型中。

FOXO1A和FOXO3A是胰岛素或胰岛素样生长因子介导的下游信号通路分子，与细胞周期、生长、凋亡以及血管新生等有密切关系。在代谢方面，它们的主要功能是平衡胰岛素的敏感性和抗性，参与癌症、自身免疫病以及心血管疾病如缺血性心脏病、心肌肥大等。田小利教授等推测FOXO3A可能通过调节胰岛素抗性和长寿相关，而FOXO1A则除调节胰岛素抗性外，可能还通过与女性生殖系统相互作用而影响人的寿命。

田小利教授研究组主要致力于寻找心血管疾病相关基因，并研究它们在心血管系统的发育、疾病及衰老过程中的作用机制。比较分析“患病与健康人群”和“长寿与普通人群”的遗传位点的异同，寻找心血管疾病致病和保护基因是重要的研究手段。在这个研究中，他们比较分析了1000个百岁老人和1000个年轻人的FOXO1A及FOXO3A基因型，得出这两个基因与长寿相关的结论。其中1000个百岁老人基因来自曾毅教授课题组1998年收集的4000份高龄老人血样。参与此研究的还有重庆第三军医大学祝之明教授、华西医科大学莫显明教授以及宁波市第一医院陈晓敏教授等。

目前北京大学健康长寿跨学科研究团队正在研究社会、行为、环境与FOXO1A及FOXO3A基因的相互作用，期望发现遗传、社会、行为、环境因素等相互作用影响老年人的健康与长寿的可能机制。

dr.qinan

Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations
Yang Li1,, Wen-Jing Wang1,, Huiqing Cao1,, Jiehua Lu8, Chong Wu1, Fang-Yuan Hu1, Jian Guo1, Ling Zhao1, Fan Yang1, Yi-Xin Zhang1, Wei Li1, Gu-Yan Zheng1, Hanbin Cui4, Xiaomin Chen5, Zhiming Zhu6, Hongbo He6, Birong Dong7, Xianming Mo7, Yi Zeng2,3,* and Xiao-Li Tian1,*
1 Department of Human Population Genetics, Institute of Molecular Medicine and 2 China Center for Economic Research, National School of Development, Peking University, 5 Yiheyuan Rd., Beijing 100871, China 3 Center for Study of Aging and Human Development, Medical School of Duke University, BUSSE Building, Duke University, Durham, NC 27710, USA, 4 Key Laboratory of Ningbo First Hospital and 5 Cardiovascular Center of Ningbo First Hospital, Ningbo University, Liuting Str. 59 Ningbo 315010, 6 Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, and 7 Department of Geriatrics, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China 8 Department of Sociology and Center for Healthy Aging and Family Studies, Peking University

* To whom correspondence should be addressed at: Department of Human Population Genetics, 316N Yingjie Conference Center, Peking University, 5 Yiheyuan Rd., Beijing 100871, China, Tel: +86 1062755397; Fax: +86 1062756926; Email: tianxiaoli@pku.edu.cn

Received July 19, 2009; Revised September 16, 2009; Accepted September 25, 2009

FOXO1A and FOXO3A are two members of the FoxO family. FOXO3A has recently been linked to human longevity in Japanese, German, and Italian populations. Here we tested the genetic contribution of FOXO1A and FOXO3A to the longevity phenotype in Han Chinese population. Six tagging SNPs from FOXO1A and FOXO3A were selected and genotyped in 1817 centenarians and younger individuals. Two SNPs of FOXO1A were found to be associated with longevity in women (P = 0.01-0.005), whereas all three SNPs of FOXO3A were associated with longevity in both genders (P = 0.005-0.001). One SNP from FOXO1A was found not to be associated with longevity. In haplotype association tests, the OR (CI95%) for haplotypes TTG and CCG of FOXO1A in association with female longevity were 0.72 (0.58-0.90) and 1.38 (1.08-1.76), P = 0.0033 and 0.0063, respectively. The haplotypes of FOXO3A were associated with longevity in men (GTC: OR (CI95%)=0.67 (0.51-0.86), P = 0.0014; CGT: OR (CI95%)=1.48 (1.12-1.94), P = 0.0035) and in women (GTC: OR (CI95%)=0.75 (0.60-0.94), P = 0.0094; CGT: OR (CI95%)=1.47 (1.16-1.86), P = 0.0009). The haplotype association tests were validated by permutation analysis. The association of FOXO1A with female longevity was replicated in 700 centenarians and younger individuals that were sampled geographically different from the original population. Thus, we demonstrate that, unlike FOXO3A, FOXO1A is more closely associated with human female longevity, suggesting that the genetic contribution to longevity trait may be affected by genders.



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The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors, and *the last two authors should be regarded as co-corresponding authors.

shenww

我进来感慨一下三个第一作者和两个通讯作者。要是全世界都那么美好，那么和睦就好了。