Association of Mitochondrial DNA Haplogroups with Exceptional Longevity in a Chinese Population

Cai1. , Xiao-feng Wang1. , Shi-lin Li1, Ji Qian1, De-gui Qian2, Fei Chen2, Ya-jun Yang1, Zi-yu Jun Xu2, Yidong Bai3, Shun-zhang Yu4, Li Jin1*

1State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China, 2Longevity Research Institute of Rugao, Jiangsu, China, 3Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America, 4School of Public Health, Fudan University, Shanghai, China

Abstract

Methodology/PrincipalFindings:To explore the effects of mtDNA haplogroups on the prevalence of extreme longevity (EL), a population based case-control study was conducted in Rugao – a prefecture city in Jiangsu, China. Case subjects include 463 individuals aged $95 yr (EL group). Control subjects include 926 individuals aged 60–69 years (elderly group) and 463 individuals aged 40–49 years (middle-aged group) randomly recruited from Rugao. We observed significant reduction of M9 haplogroups in longevity subjects (0.2%) when compared with both elderly subjects (2.2%) and middle- aged subjects (1.7%). Linear-by-linear association test revealed a significant decreasing trend of N9 frequency from middle- aged subjects (8.6%), elderly subjects (7.2%) and longevity subjects (4.8%) (p= 0.018). In subsequent analysis stratified by gender, linear-by-linear association test revealed a significant increasing trend of D4 frequency from middle-aged subjects (15.8%), elderly subjects (16.4%) and longevity subjects (21.7%) in females (p =0.025). Conversely, a significant decreasing trend of B4a frequency was observed from middle-aged subjects (4.2%), elderly subjects (3.8%) and longevity subjects

Conclusions:Our observations support the association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population.

. These authors contributed equally to this work.

Introduction

mutations [10]. However, several aging-associated accumulations of mtDNA mutations have been reported [2,3]. In particular, haplogroup D4a, D5, and D4b2b were observed to be enriched in centenarians in Japanese [11,12]. Haplogroup J was detected overrepresented in male long-living subjects and centenarians in northern Italy [13], an observation that was replicated in Irish and Finnish population [14,15], although contradicted in southern Italian [16]. These data suggest that the association between mtDNA variants and longevity could be highly geographically or population dependent, as could be seen from other genetic studies on longevity [17].

Individuals vary widely in their health status over their life course and in age at death. Longevity is thought to be a complex a puzzle of interplay of environmental, behavioral, genetic and stochastic factors. There is increasing evidence that exceptional longevity is a familial trait which is at least partially genetic. However, the magnitude of the genetic contribution is still controversial [1–3], and the inherited biological factors that promote longevity in humans remain undetermined.

Mitochondrial DNA (mtDNA) is a maternally inherited genome [4]. Human populations carry several mtDNA haplogroups defined by unique sets of mtDNA polymorphisms, reflecting mutations accumulated by a discrete maternal lineage [5,6]. Thus, haplogroup association studies have been used to assess the effect of mtDNA variants on various complex diseases such as diabetes, cancer, and Alzheimer’s disease [7–9]. Decades of evolution of the mitochondrial theory of aging have not yet clarified the

To assess the possible contribution of mtDNA haplogroup- specific mutations to the prevalence of longevity, we therefore performed a population-based case-control study in a Chinese Han population residing in Rugao, Jiangsu Province. It is worth notion that Rugao has long been claimed as a ‘longevity town’ in China since ancient time.

Materials and Methods

selected 33 mtSNPs to define 28 major mitochondrial haplogroups (D*, D4, D4a, D4b, D4b2, D4b2b, D5, M12,G*, G2, M7*, M7b, M8*, M8a, C, M9, M10, N9, N9a, A, F*, F1, B*, B5, B5a, B5b, B4a and B4b) found in the Chinese population, as shown in Table 1 [20]. These SNPs allow allocating common mitochondrial East Asian haplotypes and following the suggestion of association of 5178A with longevity from the previous studies [11,12,21–23].

Subjects