PTPN22 1858C>T (R620W) functional polymorphism and human longevity

Valerio Napolioni • Annalia Natali • Patrizia Saccucci • Nazzareno Lucarini

Received: 25 June 2010/Accepted: 17 November 2010/Published online: 27 November 2010   Springer Science+Business Media B.V. 2010

Keywords Association study  Genetic polymorphism Human longevity  Italic population  Autoimmunity

1p13, encoding lymphoid protein tyrosine phosphatase (LYP), plays a crucial role in the negative control of T lymphocyte activation. Since the age-related change in T-cell signal transduction may be one of the most impor- tant causes of cell-mediated immune response decline with ageing, we performed a population-based association study to test whether the PTPN22 1858C[T (R620W) functional polymorphism affects the ability to survive to old age and to reach even exceptional life expectancy. 892 unrelated healthy individuals (age range 8–106 years, 403 males and 489 females) from central Italy were studied. For both gender, the frequency of PTPN22*T1858 carriers does not differ significantly in nona/centenarians and in octogenar- ians respect to young group. Allele and genotype fre- quencies of age groups were compared to those reported in previously published studied carried out on control indi- viduals with Italic ancestry (N = 1393), further confirming results obtained from our sample population. Overall, our study suggests that PTPN22*T1858 allele is not negatively selected at oldest ages and we speculate that its increased ability to protect individuals against development of infectious diseases may counteract its deleterious effect on immune system leading to autoimmunity.

Introduction

It is widely accepted that cell-mediated immune functions (cytotoxicity, delayed-type hypersensitivity, etc.) decline with age [1, 2]. These age-associated immunological changes render an individual more susceptible to infection and possibly cancer, as well as to age-associated autoim- mune disorders; they may also contribute to atherosclerosis and Alzheimer’s disease [3, 4]. Recent evidences suggest that T-cell hypo-responsiveness due to defects of signaling through the T Cell Receptor (TCR) either from healthy elderly subjects or from individuals with autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus results in an impaired ability to mount efficient immune responses and to maintain responsiveness to foreign antigens [5]. This implies that a high proportion of auto-reactive T cells might accumulate either intra- thymically or in the periphery. T-cell anergy and differ- ential TCR signaling could thus also be key players in the disruption of tolerance and the onset of autoimmune diseases.

The proliferation and clonal expansion of T lympho- cytes is mostly controlled by interactions between the cytokine IL-2 and its cellular receptor [6] following TCR ligation [7]. It is now well accepted that the induction of IL-2 secretion decreases with age in mice, in rats and in humans [8]. It seems that such defects occur in the trans- duction of mitogenic signals following TCR stimulation. Indeed, recent studies suggest that alterations in, for example, tyrosine kinase activity, intracellular free cal- cium, inositol phosphates, protein kinase C (PKC), and so

V. Napolioni   A. Natali   N. Lucarini (&) Laboratory of Human Genetics, School of Biosciences and Biotechnologies, University of Camerino, Via Gentile III da Varano,

Camerino, Italy e-mail: nazzareno.lucarini@unicam.it

central Italy were studied. Information about health status was obtained for all the individuals, and no acute patholog- ical condition was present. Almost all subjects up to age of 65 were recruited in blood donor centers while those over 65 were recruited through family physicians or among guests in homes for the elderly. The population under study was divided into three group: (a) a ‘‘young group’’ ranging from 8 to 70 years (133 males and 145 females, mean age 50.7 ± 15.1), (b) ‘‘Octogenarians’’ ranging from 80 to 89 years. (180 males and 209 females, mean age 83.8 ± 2.7), and (c) ‘‘Nona/centenarians’’ ranging from 90 to 106 years (90 males and 135 females, mean age 93.0 ± 2.8). The study was approved by the Ethical Committee of the Camerino University.

on, may all contribute to changes in signal transduction with ageing [9–11]. Although the signaling machinery in T cells is extremely complicated and many steps remain to be clarified, the age-related change in T-cell signal transduc- tion may be one of the most important causes of cell- mediated immune response decline with ageing.