Association analysis of the SHC1 gene locus with longevity in the Japanese population

Received: 18 June 2003 / Accepted: 12 August 2003 / Published online: 2 October 2003 ©: Springer-Verlag 2003

Hidehiko Kamei Toshio Kojima received his D.D.S. degree is presently a Team Leader of from the School of Dentistry, the Human Genome Research Aichi-gakuin University, Ja- Group RIKEN Genomic Sci- pan. He is presently a trainee of ences Center. His research in- the Human Genome Research terests include genetic analyses Group at RIKEN and a gradu- of centenarians and human ate student of the Department diseases. He is also interested of Periodontology, School of in comparative genomics es- Dentistry, Aichi-gakuin Uni- pecially focusing on primates. versity. His research interests include the relationship be- tween genetic polymorphisms and human aging and also genetic risk factors of peri- odontal disease.   

 

Abstract The SHC1 gene encodes a signaling and transforming protein that has been implicated in the aging process in worms and mammals. In this study we examined 230 Japanese centenarians and 180 healthy younger controls and looked at the SHC1 locus as a candidate region that may be associated with longevity. We identified 12 single nucleotide polymorphisms (SNPs) within a 10-kb region encompassing the entire SHC1 gene from the DNA of 30 centenarians and 24 healthy younger controls. Five SNPs, including three nonsynonymous sites, lay within coding elements, six were located within introns, and one was in the 30 untranslated region. All of these SNPs were relatively rare, with a minor allele frequency of less than 5% in our

Department of Periodontology, School of Dentistry, Aichi-gakuin University, 2-11 Suemori-dori, Chikusa-ku, Nagoya, Aichi, 464-8651,

Y. Arai · K. Yamamura · M. Takayama · S. Nakazawa · Y. Ebihara N. Hirose Department of Geriatric Medicine, School of Medicine, Keio University,

Shinanomachi, Shinjyuku-ku, Tokyo,

-

, Japan

subjects. A pairwise linkage disequilibrium analysis using the r2 statistic showed that two of the SNP pairs are in tight linkage disequilibrium at this locus. We investigated the possible association of SHC1 with longevity using association analyses with allelotypes and haplotypes but found that the SNPs identified in SHC1 had no impact on longevity for Japanese centenarians.

Y. Gondo

Y. Sakaki

Materials and methods

Subjects

A total of 230 Japanese centenarians (168 women, 62 men, age 100.8€1.5 years) living in the Tokyo metropolitan area recruited between April 1999 and January 2001 for the second of the Tokyo Centenarian Study. Participants were identified the national registry of centenarians, published by the Ministry Health, Welfare, and Labor [11]. Among those enrolled 162 living at home, and 68 were institutionalized. None was in an care setting, and none was receiving tube feeding. included physical examination, measurement of body weight height, electrocardiography, and blood pressure Information regarding habitual food intake, alcohol smoking habits, physical and cognitive functioning, use of ication, and past medical history was also collected [11]. seven centenarians (20.4%) were receiving antihypertensive ment, and ten had a history of treatment for cancer (two cancer, two colon, two prostate, one bladder, two breast, and cancer of the uterus). Using the Mini-Mental State (MMSE) and clinical dementia rating criteria, 170 (73.9%) were found to have varying degrees of cognitive ment; this rate is similar to that of a previous study in Japan The regionally matched control subjects comprised 180 volunteers (116 women, 64 men, mean age 36.1€11.3 years, 22–65) who were recruited from hospital and institutional medical and nursing school students, and bank clerks. The subjects were free from diseases such as coronary artery stroke, diabetes, and cancer. Smoking and alcohol consumption moderate to nil. All subjects enrolled in this study were Nonfasting venous blood (20 ml) was collected from all and genomic DNA was prepared from peripheral according to standard protocols. Written informed consent obtained from all participants directly or by proxy. This study approved by the ethics committees of the Medical School of University and of the RIKEN Yokohama Institute.

Introduction

The influence of genes on aging and life expectancy is well established in species ranging from yeast to mammals. The shc1 gene was originally described as a proto-oncogene, encoding three different isoforms of shc1 proteins with molecular masses of 46, 52, and 66 kDa respectively [1]. Recently an unexpected correlation between life span and control of the oxidative stress response was reported. Targeted mutation of the shc1 gene locus caused ablation of a splice variant of relative molecular mass 66,000 (p66shc) and resulted in selective resistance to oxidative stress and an extended life span in the mouse [2]. On a high-fat diet, the p66shc(cid:1)/(cid:1) mouse showed a significant reduction in systemic and tissue oxidative stress, vascular cell apoptosis, and early atherosclerotic lesions, compared with the wild type animal [3]. Another recent study [4] suggested an important functional relationship between forkhead proteins, shc1, and intracellular oxidants, all of which are thought to be involved in the aging process in worms [5, 6] and mammals [7, 8]. These studies suggest a role for shc1 in the interrelation between oxidants, stress, and aging.