The 308 (G/A) single nucleotide polymorphism in the TNF-a gene and the risk of major depression in the elderly Anna Paola Cerri 1 , Beatrice Arosio 2 , Chiara Viazzoli 2 , Roberto Confalonieri 1 , Carlo Vergani 2 and Giorgio Annoni 1 1 Department of Clinical Medicine and Prevention, A.O. San Gerardo, University of Milan-Bicocca, Monza, Milan, Italy 2 Department of Internal Medicine, University of Milan, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Fondazione IRCCS Milan, Italy Correspondence to: G. Annoni, MD, E-mail: giorgio.annoni@unimib.it Objective: The immune system (IS) plays a key role in the mechanisms underlying major depression (MD) and pro-inflammatory cytokines seem to be particularly involved in the pathogenesis of the disease. There is growing evidence of a relationship between commonly studied single nucleotide polymorphisms (SNPs) in cytokine genes and an increased risk of MD. The aim of our study was to investigate the association between the 308(G/A) SNP in the tumour necrosis factor-a (TNF-a) gene and late-life MD in elderly people without dementia. Methods: Blood samples were obtained from 50 subjects enrolled at the Geriatric Department of the San Gerardo Hospital in Monza, Italy, after screening with the geriatric depression scale (GDS  15) and mini-mental state evaluation (MMSE  24). The 308 (G/A) SNP was genotyped by SSP-PCR amplification. Two hundred and forty age-matched healthy volunteers were taken as the control group. Results: Genotype and allele distributions in patients with MD were significantly different from those of the controls. In subjects affected by MD we found a higher percentage of the GG genotype (84 vs. 68,3%; p ¼ 0.007) and thus of the G allele (92 vs. 81,9%; p ¼ 0.05). The GG genotype was associated with a greater risk of developing the disease (OR 2.433, CI 1.09–5.43). Conclusions: Our study suggests that the 308 (G/A) polymorphism in the TNF-a gene could play a role in determining susceptibility to MD. An activation of the TNF-a system could contribute to the development of MD in the elderly. Copyright # 2009 John Wiley & Sons, Ltd. Key words: major depression; inflammation; TNF-a; gene polymorphisms History: Received 28 October 2008; Accepted 28 April 2009; Published online 17 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/gps.2323 Introduction Major depression (MD) is a main clinical issue in elderly people. It affects almost 10% of adults over 65 years of age who are seen in primary care settings and has a number of important consequences: it influences quality of life, reduces effective daily functioning and ultimately leads to an increased use of health services. Yet, MD is often underdiagnosed and undertreated in the elderly since age is a crucial variable that can make its clinical manifestations more difficult to recognize. It is generally acknowledged that MD is a complex disorder involving both genetic and environmental influences, with the immune system (IS) playing a key role in its pathogenesis. It has in fact been shown that in the normal development of the central nervous system (CNS) as well as in the pathogenesis of neuropsychiatric disorders there is an involvement of the inflammatory response and more specifically of cytokines, which act directly on neuronal cells or modulate neurotrasmitter and neuropeptide systems (Schiepers et al., 2005; Anis- man et al., 2008). RESEARCH ARTICLE Copyright # 2009 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2010; 25: 219–223.