نقش تنوع ژن VEGF در طول عمر: درس از جمعیت ایتالیا

Vascular endothelial growth factor (VEGF) gene polymorphisms have been associated with an increased risk of developing a wide variety of disorders from diabetes to neurodegenerative diseases suggesting functions not confined to its vascular effects originally described. Based on the VEGF protective roles undisclosed in pathological conditions, we evaluate whether VEGF variability might be a determinant also for longevity. Four polymorphisms (−2578C/A, −1190G/A, −1154G/A and −634G/C) within the VEGF gene promoter region in 490 unrelated Italian healthy subjects have been analysed. Significant changes of allele, genotype (−2578/AA versus −2578/CC: OR = 2.08, p = 0.007; −1190/AA versus −1190/GG: OR = 2.01, p = 0.011) and haplotype (AAGG: 10.4% versus 14.9%, p = 0.03) frequency distributions were observed between young/elderly (25–84 years old) and long-lived (85–99 years old) subjects. These results suggest that VEGF gene variability can be inserted among the genetic factors influencing the lifespan.

Longevity represents a very complex phenomenon due to the interaction among genetic, environmental and lifestyle factors. Identification of genetic and non-genetic factors involved in aging has progressed extensively in the recent years because of increased interest in defining the determinants of human life expectancy. It has been suggested that genes and biochemical factors likely to be implicated in aging-related disorders may have an important role also in human longevity. Among genetic markers, several variants in pro- or anti-inflammatory cytokines and in vascular factors have been shown to affect successful aging and longevity (Panza et al., 2004 and Salvioli et al., 2006). Vascular endothelial growth factor (VEGF) is an important angiogenesis cytokine that undergoes transcriptional and post-transcriptional induction by hypoxia. It has been implicated in several pathological conditions, from tumour proliferation to inflammatory and ischemic processes (Carmeliet, 2003 and Ferrara et al., 2003). VEGF has been originally identified on the basis of its vascular effects, but recently has been recognised as an important signalling molecule in the nervous system, as well as in neurodegenerative disorders and in peripheral neuropathies (Rosenstein and Krum, 2004 and Storkebaum and Carmeliet, 2004). An age-dependent decline in VEGF expression has been reported in different tissues, however the molecular alterations responsible for this reduction have not been elucidated. A number of polymorphisms localised within the VEGF gene promoter region have been linked to increased susceptibility to multiple angiogenesis-dependent diseases and age-related neurological disorders in humans (Del Bo et al., 2005 and Lambrechts et al., 2003). Individuals homozygous for the haplotypes involving the −2578AA, −1154A/G and −634GG variants had lower serum VEGF levels and increased risk of developing amyotrophic lateral sclerosis (ALS). C(−2578)A, C(−1198)T, G(−1190)A and G(−1154)A polymorphisms have been correlated with the risk of developing Alzheimer's disease (AD). In addition, the same polymorphisms are able to alter basal and post-stimulation promoter activity in human transfected MCF7 cells (Stevens et al., 2003). Finally, an association has been reported between −1154 and −2578 genotypes and VEGF production in the peripheral blood mononucleated cells of healthy subjects (Shahbazi et al., 2002). All these effects are dependent on several sequence polymorphisms, suggesting that VEGF gene variability may contribute to the inherited predisposition to VEGF-mediated pathological conditions. Aim of the present study is to explore the VEGF gene promoter variability as a genetic determinant for longevity in an Italian population.