Contents lists available at ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/issn/10434666  

journal homepage: www.elsevier.com/locate/issn/10434666

and gender-specific epistasis between ADA and TNF-a influences

Valerio Napolioni a,b,c, , Francesco M. Carpi c, Paola Giannì c, Roberto Sacco a,b, Luca Di Blasio c, Fiorenzo Mignini d, Nazzareno Lucarini c, Antonio M. Persico a,b

of Molecular Psychiatry and Neurogenetics, University ‘‘Campus Bio-Medico’’, Rome, Italy bLaboratory of Molecular Psychiatry and Psychiatric Genetics, Department of Experimental Neurosciences, I.R.C.C.S. ‘‘Fondazione Santa Lucia’’, Rome, Italy cSchool of Biosciences and Biotechnologies, University of Camerino, Camerino, Italy dSchool of Pharmacy and Health Products, University of Camerino, Camerino, Italy



Aging is a complex phenotype with multiple determinants but a strong genetic component impacts on survival to extreme ages. The dysregulation of immune responses occurring with age is believed to contribute to human morbidity and mortality. Conversely, some genetic of successful aging might reside in those polymorphisms for the immune system genes immune responses. Here we examined the main effects of single loci and multi-locus interactions to the hypothesis that the adenosine deaminase (ADA) and tumor necrosis factor alpha (TNF-a) genes influence human life-expectancy. ADA (22G>A, rs73598374) and TNF-a ((cid:2)308G>A, rs1800629; rs361525) functional SNPs have been determined for 1071 unrelated healthy individuals from Italy (18–106 years old) divided into three gender-specific age classes defined according to information and accounting for the different survivals between sexes: for men (women), the first consists of individuals <66 years old (<73 years old), the second class of individuals 66–88 years (73–91 years old), and the third class of individuals > 88 years old (>91 years old). Single-locus showed that only ADA 22G>A is significantly associated with human life-expectancy in males ison 1 (age class 2 vs. age class 1), O.R. 1.943, P = 0.036; comparison 2 (age class 3 vs. age class 2), 0.320, P = 0.0056). Age- and gender-specific patterns of epistasis between ADA and TNF-a were using Generalized Multifactor Dimensionality Reduction (GMDR). In comparison 1, a significant interaction occurs in females between ADA 22G>A and TNF-a (cid:2)238G>A (Sign Test P = 0.011). In ison 2, both two-loci and three-loci interaction are significant associated with increased over 88 years in males. In conclusion, we report that a combination of functional SNPs within ADA and TNF-a genes can influence life-expectancy in a gender-specific manner and that males and females different pathways to attain longevity.

 2011 Elsevier Ltd. All rights reserved.

1. Introduction

The dysregulation of both immune and inflammatory responses occurring with increasing age is believed to substantially contrib- ute to morbidity and mortality in humans [2–4]. Conversely, hu- man longevity seems to be directly correlated with optimal functioning of the immune system [5], suggesting that some genet- ic determinants of successful ageing might reside in those poly- morphisms for the immune system genes that regulate immune responses [6]. In this context, tumor necrosis factor alpha (TNF-a, gene map locus 6p21.3, within the major histocompatibility complex class III region) is one of the most studied genes. It encodes for a pleiotropic cytokine playing a key role in both inflammation and chronic age related diseases. The TNF-a (cid:2)308G>A (rs1800629) Single Nucleotide Polymorphism (SNP) has received a particularly large amount of attention because of its putative effect on TNF-a expression. Some in vitro studies indicated

Human longevity is a complex trait arising from the interplay of environmental and genetic factors. The study of such phenotype gives us the opportunity to uncover the biological determinants of human survival and life-expectancy. In fact, most of the infor- mation regarding the genetics of human longevity has been ob- tained through retrospective studies, under the hypothesis that unfavorable genotypes should be dropped out of the population by a sort of ‘‘demographic selection’’ [1] which finally results in an enrichment of favorable genotypes in the gene pool of long living people.

Correspondingauthorat:LaboratoryofMolecularPsychiatryandNeurogenetics, University ‘‘Campus Bio-Medico’’, Rome, Italy.

population from 1890 onward (computed using death counts per calendar year and per year of birth as reported for the Italian pop- ulation in the Human Mortality Database, available online at www.mortality.org) [25]. The study protocol was approved by the Joint Ethical Committee (JEC) University of Camerino-Azienda ASUR Marche ZT-10 Camerino, in accordance with the Declaration of Helsinki in its revised edition and with international and local regulatory requirements.

transcription activity compared to the G⁄/G⁄ genotype [7]. There- fore, many investigators have examined the contribution of the (cid:2)308G>A SNP in human longevity and age-related diseases [8,9]. However, while correlation between the TNF-a 308G>A SNP and age-related or autoimmune pathologies has been established [9], the association studies on human longevity have yield contrasting results [8,10–15]. Interestingly, the TNF-a gene expression seems to be influenced also by the (cid:2)238G>A SNP (rs361525) in its pro- moter region: carriers of hypomorphic TNF-a (cid:2)238⁄A allele display a reduced expression [16], thus eventually counteracting the effect of (cid:2)308G>A SNP.

2.2. ADA and TNFa SNPs genotyping