below.

Genetic association of FOXO1A and FOXO3A with 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,* 

1 Department of Human Population Genetics, Institute of Molecular Medicine,
Peking University 
2 China Center for Economic Research,
National School of Development,
Peking University 
3 Department of Sociology and Center for Healthy Aging and Family Studies,
Peking University 
5 Key Laboratory of Ningbo First Hospital and 6Cardiovascular Center of Ningbo First Hospital,
Ningbo University 
7 Center for Hypertension and Metabolic Diseases,
Department of Hypertension and Endocrinology,
Daping Hospital,
Third Military Medical University,
Chongqing Institute of Hypertension 
8 Department of Geriatrics,
West China Hospital,
West China Medical School,
Sichuan University

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 not 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 = 0.0033 and 0.0063, respectively. The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) = 0.67 (0.51-0.86), P = 0.0014; CGT: OR (95% CI) = 1.48 (1.12-1.94), P = 0.0035] and in women [GTC: OR (95% CI) = 0.75 (0.60-0.94), P = 0.0094; CGT: OR (95% CI) = 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 a sample of 700 centenarians and younger individuals that were 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 gender.

INTRODUCTION

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 past decades. A twin-based study suggested that genetic components may account for over 25% of the variation in the longevity trait (3). Later, it was found that genetic factors have increasing effects, particularly after the age of 60 (4). Although longevity may not correlate perfectly with health, centenarians have a lower risk of cardiovascular disease and live significantly longer than non-centenarians. This suggests that genetic contributions to longevity are, at least in part, due to protective effects against disease. Therefore, the search for longevity-associated genes should not only lead to an understanding of the fundamental aspects of human aging but also to the identification of new targets beneficial for medical care.

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 lifespanIn Table 1, the differences between the case and control groups for the listed parameters were evaluated by Student's t-test. A P-value less than 0.05 was considered statistically significant. Single SNP association analysis was conducted on six SNPs (rs17630266, rs2755209, and rs2755213 for FOXO1A; rs2253310, rs2802292, and rs4946936 for FOXO3A) by direct sequencing in all selected individuals. No significant deviation from the Hardy-Weinberg equilibrium test was found for all six SNPs in both populations. In sex-combined centenarians and controls, except for SNP rs17630266, the minor allele frequencies (MAFs) of both rs2755209 and rs2755213 of FOXO1A were significantly lower in the centenarian group than in control. In addition to genetic and environmental factors, gender also has a strong effect on the human longevity phenotype. It is well-known that females have a longer life than males (25). A number of studies have documented that females account for a much larger percentage of the centenarian population (26). In the 1998 baseline survey of the Longitudinal Healthy Longevity Study (CLHLS), we found that the ratio of males to females in centenarians is 1:4 (Table 1).

Table 1 presents the characteristics of populations including case (n=761) and control (n=1056) for population 1, and case (n=350) and control (n=350) for population 2. The data are presented as mean+SEM (standard error of the mean). P-values are calculated from t-test comparing case and control groups within population. Case refers to centenarians while control refers to individuals from general population. The table lists gender (m/f), age, body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP).