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 the vast differences among ethnicities. We analyzed in 128 Italian long-lived individ- uals and 150 unrelated healthy subjects, the recently reported association between rs189037 in the ataxia- telangiectasia mutated gene promoter and longevity in Chinese nonagenarians/centenarians. 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, in order to reach reliable conclusions on the real effect that candidate genes have on longevity.

centenarians is 1 in 10,000. However, this number is increasing rapidly due to changes in diet, other environ- mental factors and, last but not least, the possibility to recover from diseases [2]. Furthermore, studies have been performed to evaluate the role genetic factors play in exceptional longevity [1–3], but only the apolipoprotein E (ApoE) gene has been replicated and confirmed in several populations [4, 5]. This could be due to the great differ- ences 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].

genetic variant (rs189037) in the ataxia-telangiectasia muta- ted (ATM) gene promoter and longevity in Chinese non- agenarians/centenarians. 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 lon- gevityandhasaneffectonATMtranscription,aswell.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 polymor-

Introduction

The average human lifespan in developed countries ranges from about 80 to 85 years [1], and the frequency of

phism 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;

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).

52.3 % aged100 years)and 150 unrelated healthy subjects, as a control group, (56.7 % females, mean age at examination 67.2 ± 9.1 years) (Table 1).

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 the 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.

The LLI group was divided into two subgroups (\100 years and C100 years, the latter considered cente- narians), and we did find a statistically significant differ- ence in the C/T genotype in centenarians compared to the controls (p = 0.037) (Table 2).

The rs189037 genotype and allele distributions were in the Hardy–Weinberg (HW) equilibrium in the control group (p = 0.59), but not in the LLI group (p = 0.03). This could be attributed to the centenarians group (p = 0.028), providing further evidence of the association of the locus with longevity. Indeed, if genotype distribution does not follow the HW equilibrium in the control popu- lation, this indicates that the results should be treated with caution. However, if it is the studied population that does not follow the HW equilibrium, as in this case, this may confirm a correlation between the investigated genetic locus and longevity.

DNA was extracted from white blood cells using the phenol–chloroform procedure and all genotyping was performed by KBioscience, Ltd., which uses their own fluorescence-based competitive allele-specific PCR system (KASPar) assay. Accuracy [99 % was achieved and rou- tine quality control measures were performed on all genotyping (http://www.kbioscience.co.uk/). Odds ratio (OR) and corresponding 95 % confidence intervals (CIs) were calculated using logistic regression models adjusted for gender and age. A power analysis was performed using COMPARE2 software (http://www.brixtonhealth.com/). Comparisons of genotype and allele frequencies were performed using the v2 test.

Discussion