Genetic association of FOXO1A and FOXO3A longevity trait in Han Chinese populations

Yang Li1,{ , Wen-Jing Wang1,{ , Huiqing Cao1,{ , Jiehua Lu3, Chong Wu1, Fang-Yuan Hu1, Jian Ling Zhao1, Fan Yang1, Yi-Xin Zhang1, Wei Li1, Gu-Yan Zheng1, Hanbin Cui5, Xiaomin Chen6, Zhiming Zhu7, Hongbo He7, Birong Dong8, Xianming Mo8, Yi Zeng2,4,{ and Xiao-Li Tian1,(cid:2),{

1Department of Human Population Genetics, Institute of Molecular Medicine, 2China Center for Economic Research, National School of Development, Peking University and 3Department of Sociology and Center for Healthy Aging and Family Studies, Peking University, 5 Yiheyuan Rd., Beijing 100871, China, 4Center for Study of Aging and Human Development, Medical School of Duke University, Duke University, BUSSE Building, Durham, NC 27710, USA, 5Key Laboratory of Ningbo First Hospital and 6Cardiovascular Center of Ningbo First Hospital, Ningbo University, Liuting Str. 59, Ningbo 315010, China, 7Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China and 8Department of Geriatrics, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China

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 5 0.01–0.005), whereas all three SNPs of FOXO3A were associated with longevity in both genders (P 5 0.005–0.001). One SNP from FOXO1A was found not to be associated with longevity. In haplotype association tests, the OR (95% CI) 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 5 0.0033 and 0.0063, respectively. The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) 5 0.67 (0.51–0.86), P 5 0.0014; CGT: OR (95% CI) 5 1.48 (1.12–1.94), P 5 0.0035] and in women [GTC: OR (95% CI) 5 0.75 (0.60–0.94), P 5 0.0094; CGT: OR (95% CI) 5 1.47 (1.16–1.86), P 5 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.

INTRODUCTION

past decades. A twin-based study suggested that genetic com- ponents may account for (cid:2)25% of the variation in the longev- ity trait (3). Later, it was found that genetic factors have increasing effects, particularly after the age of 60 (4). Though longevity may not correlate perfectly with health

Human longevity is a complex trait affected by both genetic and environmental factors (1,2). How the genetic determinants contribute to longevity has provoked great interest over the

whom correspondence should be addressed at: Department of Human Population Genetics, 316N Yingjie Conference Center, Peking 5 Yiheyuan Rd., Beijing 100871, China. Tel: þ86 1062755397; Fax: þ86 1062756926; Email: tianxiaoli@pku.edu.cn †The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors. ‡The last two authors should be regarded as co-corresponding authors.

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On the other hand, gender effects on longevity can be modified by both genetic and environmental factors (28,29), but how genetic determinants interact with gender and play a role in longevity is not fully understood (30). Previously, it was shown that increased dFOXO, a form of FoxOs in D. melanogaster, extends female lifespan and reduces fecund- ity (21). In human, FOXO3A has been associated with expended lifespan in both genders. It remains to be determined whether FOXO1A is associated with human longevity.

centenarians have a lower risk of cardiovascular disease live significantly longer than those of non-centenarians This suggests that genetic contributions to longevity are, least in part, due to protective effects against disease. fore, the search for longevity-associated genes should not only to an understanding of the fundamental of human aging but also to the identification of new targets beneficial for medical care.

In the present study, we examined the association of FOXO1A and FOXO3A with the longevity phenotype in Han Chinese. We demonstrated that FOXO1A is more closely associated with female than with male longevity, whereas FOXO3A is associated with longevity in both genders. Thus, our study provides a new insight into the genetic mechanism of human longevity.