Mechanisms of Ageing and Development 123 (2002) 1403-1410 / www.elsevier.com/locate/mechagedev

Influences on human longevity by polymorphism (Tyrosine Hydroxylase gene): a relative risk approach

Qihua Tan, D. Bellizzi, G. Rose, S. Garasto, C. Franceschi, T. Kruse, J.W. Vaupel, G. De Benedictis, A.I. Yashin*

a Department of Clinical Biochemistry and Genetics, KKA, Odense University Hospital, Odense
b Cell Biology Department, University of Calabria, Rende, Italy
d Max-Planck Institute for Demographic Research, Doberaner Str. 114, 18057 Rostock, Germany
e Center for Demographic Studies and Sanford Institute, Duke University, Durham, NC, USA

Received 27 February 2002; received in revised form 1 July 2002; accepted 17 July 2002

Abstract

A new method based on the recently developed relative risk approach is introduced and applied to data from Italian centenarian study (965 subjects aged from 13 to 109 years old) for investigating influences on longevity by Tyrosine Hydroxylase (TH) gene variability. The strategic parameterization enables the model to disentangle the various ways by which HUMTHO1.STR alleles (alleles 6, 7, 8, 9, 10*, 10 as defined according to the number of repeats) may contribute to reducing or increasing the hazard of death with different patterns of influence. Among all the alleles, we have found that allele 10* (10 imperfect repeats) shows a remarkable dominant and beneficial effect that reduces the log hazard of death in an additive manner. The results confirm that HUMTHO1.STR polymorphism is involved in the modulation of human longevity.

Keywords: TH gene; Relative risk; Polymorphism; Longevity

1. Introduction

Lifespan is a complex trait shaped by genetic, environmental, and stochastic factors. The genetic component has been intensively investigated by correlation studies in twins (McGue et al., 1993). Increasing evidence shows that, as in model organisms, the capability to cope with stress in humans is also a leading factor in the rate and quality of aging (Franceschi et al., 2000). Therefore, all genes involved in the complex mechanisms that control stress response are candidate genes for longevity. 

The Tyrosine Hydroxylase (TH) gene (11p15.5) encodes TH, the rate-limiting enzyme in the synthesis of catecholamines, amino acid-derived molecules produced by the sympathetic nervous system in response to stress. An STR marker (HUMTHO1.STR) lies inside TH intron 1 (Polymeropoulos et al., 1991), a region which is involved in RNA alternative splicing of the TH primary transcript for generating four tissue-specific types of mRNA (Kobayashi et al., 1988). Association between HUMTHO1 variability and longevity was first observed (De Benedictis et al., 1998). Thereafter, gene-environment interactions and sex-specific genetic effects have been observed when HUMTHO1 variability was analyzed by models that combine genotypic and demographic information in the estimation of genetic influence on lifespan (Tan et al., 2001b). The involvement of the 11p15.5 chromosomal region in the longevity phenotype has been confirmed by linkage disequilibrium studies carried out by analyses of two other polymorphic genes occurring in the same chromosomal region: Insulin and Insulin Growth Factor 2 (De Luca et al., 2001). However, the effects of HUMTHO1.STR allele-allele interactions on hazard of death and longevity have not been analyzed until now. The aim of the present study is to introduce an analytical method that permits disentangling the effects of HUMTHO1.STR alleles on the longevity trait. The results confirm that this polymorphism is involved in the modulation of human longevity and that allele-allele interaction plays an important role.

2. Materials and methods

2.1. Samples

The data used in this study is an updated version of the data by which TH gene/longevity association was first discovered (De Benedictis et al., 1998). All individuals in the sample are unrelated, clinically healthy, and are from various socioeconomic backgrounds. For each individual, origin and residence in Italy were checked by interview as far as the grandparents' generations. All individuals gave informed consent prior to their inclusion in the study. A total of 965 subjects were collected in the new update. Among them, 210 are centenarians who were over 100 years old when a blood sampleal. (2001b), and Tan et al. (2001c).

The text has several spelling, grammatical, and formatting errors. Here's the corrected text:

The distribution of subjects according to age group, sex, and HUMTHO1.STR genotype is shown in Table 2. For each allele, the estimated initial allele frequency and the relative risks by genotype are presented. Significance levels for risk parameters (relative risks for the allele and for gene-sex interaction) were determined by testing the statistical differences between the estimated risks and 1, with the null hypothesis H:r=1. The probability of a Type I error is 0.05. 

Allele 10* is interesting in that both heterozygous and homozygous genotypes display beneficial influences that reduce the carriers' hazards of death. Corresponding relative risks are 0.920 (p-value=0.013) and 0.851 (p-value=0.005) for the heterozygous and homozygous genotypes, respectively. However, after correction for multiple comparisons, we obtain a probability of making type I error of 0.076 for the risk of allele 10* heterozygous genotype, which is borderline significant, while the risk for the 10*10* homozygous genotype remains significant (p-value=0.030). Interestingly, the relative risk of males and females is obtainable from population statistics.