Ataxia-telangiectasia mutated (ATM) genetic variant in Italian centenarians

Irene Piaceri, Silvia Bagnoli, Andrea Tedde, Sandro Sorbi, Benedetta Nacmias

Received: 29 June 2012 / Accepted: 29 August 2012 / Published online: 9 September 2012

Springer-Verlag 2012

Abstract

Lifespan is attributable to genetic factors, and some studies have attempted to identify putative genes implicated in human longevity. Several genetic loci have been associated with longevity, but some of these are not replicable, probably due to vast differences among ethnicities. We analyzed the recently reported association between rs189037 in the ataxia-telangiectasia mutated gene promoter and longevity in Chinese nonagenarians/centenarians in 128 Italian long-lived individuals and 150 unrelated healthy subjects. Our study confirms the association between the rs189037 C/T genotype and longevity in Italian centenarians, with an odds ratio of 1.85 (95 % CI 0.99-3.45). To understand the genetic basis for longevity is an extraordinarily difficult task, and therefore it is important to replicate any positive findings, especially if detected in other ethnic groups, to reach reliable conclusions on the real effect that candidate genes have on longevity.

The frequency of centenarians is 1 in 10,000. However, this number is increasing rapidly due to changes in diet, other environmental factors and the possibility to recover from diseases [2]. Furthermore, studies have been performed to evaluate the role genetic factors play in exceptional longevity [13], but only the apolipoprotein E (ApoE) gene has been replicated and confirmed in several populations [4, 5]. This could be due to the great differences in allele and genotype frequencies in the studied polymorphisms among ethnicities [2, 6].

Following the ApoE association with longevity, the most studied pathway has been the lipid metabolism, but there is some evidence that extreme longevity could be associated with increased resistance to oxidative stress [6, 7]. A genetic variant (rs189037) in the ataxia-telangiectasia mutated (ATM) gene promoter and longevity in Chinese nonagenarians/centenarians were recently reported. The encoded protein is important in the resistance to oxidative stress through its role in the detection of reactive oxygen species lesions and DNA repair defects [9, 10]. Chen's study [8] demonstrated that the rs189037C/T genotype is significantly associated with longevity and has an effect on ATM transcription. Indeed, the study showed that the C/T genotype is associated with moderate levels of ATM gene expression, suggesting that the best way to prolong lifespan is via a moderate level of ATM. In light of these findings, we analyzed ATM polymorphism distribution in Italian long-lived individuals (LLIs) to confirm the role the ATM gene plays in our population.

Materials and methods

Our study group consisted of 278 Italian subjects: 128 LLIs (78.1 % females, mean age at examination 98.7 ± 5.1 years; 52.3 % aged 100 years) and 150 unrelated healthy subjects as a control group (56.7 % females, mean age at examination 67.2 ± 9.1 years). All subjects were enrolled at the Neurology Unit of the Department of Neurological and Psychiatric Sciences of the University of Florence. The control group was carefully assessed using a rigorous clinical history evaluation and were interviewed to exclude the presence of relatives of past generations with exceptional longevity.

The LLIs were recruited from the same geographical area and were in good health, relative to their very advanced age, and did not present more common age-related pathologies (e.g., severe physical impairment, clinically evident cancer or renal insufficiency), although many had decreased auditory and visual acuity, as observed in other studies on healthy LLIs [3, 11]. Informed consent for genetic screening was obtained from the study participants, and the study protocol was approved by the local ethics committee and conducted in accordance with the provisions of the Helsinki Declaration.

Results

We examined the distribution of the C/T genotype frequencies with respect to the other genotypes (C/C or T/T) in the LLI group compared to the controls, due to a dose-dependent effect of this genotype on ATM production [8]. We did not find any significant difference in the distribution of C/T genotypes in the LLI group compared to the controls (p = 0.12) (Table 2).

The LLI group was divided into two subgroups (less than 100 years and 100 years old or more, the latter considered centenarians), and we did find a statistically significant difference in the C/T genotype in centenarians compared to the controls (p = 0.037) (