Cytokine Polymorphisms in the Pathophysiology of Mood Disorders Mario Clerici, MD, Beatrice Arosio, PhD, Emanuela Mundo, MD, Elisabetta Cattaneo, MD, Sara Pozzoli, MD, PhD, Bernardo Dell’Osso, MD, Carlo Vergani, MD, Daria Trabattoni, PhD, and A. Carlo Altamura, MD Original Research Prof. Clerici is head of the Department of Biomedical Sciences and Technologies at the University of Milan, Italy and scientific director of the IRCCS S. Maria Nascente, Fondazione Don Gnocci, in Milan, Italy. Dr. Arosio is scientific researcher in the Department of Internal Medicine, Geriatric Unit, IRCCS Fondazione, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Italy. Dr. Mundo is a member of the faculty of psychology at La Sapienza, University of Rome, Italy. Dr. Cattaneo is a psychiatrist in the Department of Psychiatry IRCCS Fondazione, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Italy. Dr. Pozzoli is a psychiatrist in the Department of Psychiatry IRCCS Fondazione, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Italy. Dr. Dell’Osso is a psychiatrist in the Department of Psychiatry IRCCS Fondazione, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Italy. Prof. Vergani is chair of geriatrics in the Department of Internal Medicine, Geriatric Unit, IRCCS Fondazione, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Italy. Prof. Trabattoni is associate profes- sor and chair of immunology in DISP LITA Vialba at the University of Milan, Italy. Prof. Altamura is chair of psychiatry in the Department of Psychiatry IRCCS Fondazione, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Italy. Faculty Disclosures: Prof. Altamura is a consultant to AstraZeneca and Merck; and is on the speaker’s bureau of Eli Lilly, Pfizer, and Sanofi. Professors Clerici and Vergani, and Drs. Arosio, Mundo, Cattaneo, Pozzoli, Dell’Osso, and Trabattoni do not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Funding/Support: This research was partially funded by a University Grant. Submitted for publication: March 2, 2009; Accepted for publication: June 26, 2009. Please direct all correspondence to: Bernardo Dell’Osso, MD, IRCCS Fondazione, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via Francesco Sforza 35, 20122 Milan; Tel: 02-5503-5982, Fax: 02-503-20310; e-mail: bernardo.dellosso@policlinico.mi.it. ABSTRACT Introduction:฀An฀increasing฀amount฀of฀data฀ suggests฀that฀dysregulation฀of฀the฀immune฀sys- tem,฀including฀the฀cytokine฀network,฀is฀associ- ated฀with฀the฀etiology฀and฀pathophysiology฀of฀ mood฀disorders.฀Genes฀encoding฀cytokines฀are฀ highly฀polymorphic฀and฀single฀nucleotide฀poly- morphisms,฀associated฀with฀increased฀or฀reduced฀ cytokine฀production,฀have฀been฀described.฀The฀ aim฀of฀this฀study฀was฀to฀define฀the฀genetic฀immu- nologic฀scenario฀associated฀with฀major฀depres- sive฀disorder฀(MDD)฀and฀bipolar฀disorder.฀ Methods:฀ Eighty-four฀Italian฀outpatients฀ affected฀by฀bipolar฀disorder฀type฀I,฀bipolar฀dis- order฀type฀II,฀or฀MDD,฀and฀363฀healthy฀controls฀ were฀enrolled฀into฀the฀study.฀We฀analyzed฀allele฀ and฀genotype฀distribution฀of฀–308฀(G/A)฀tumor฀ necrosis฀factor- α฀(TNF- α),฀+874฀(T/A)฀inter- feron-γ (IFN-γ), -174฀(G/C)฀interleukin฀(IL)-6,฀and฀ –1082฀(G/A)฀IL-10฀promoter฀polymorphisms฀by฀ CNS Spectr 14:8 © MBL Communications Inc. August 2009 419 FOCUS POINTS • Accumulating evidence indicates the existence of reciprocal communication pathways between nervous, endocrine, and immune systems. • Dysregulation of the immune system, including the cytokine network, is associated with the eti- ology and pathophysiology of mood disorders. • Cytokines initiate immune processes and modu- late monoamine neurotransmission within the central nervous system. Polymerase฀Chain฀Reaction฀Sequence฀Specific฀ Primers฀technique. Results:฀We฀observed฀different฀genotype฀and฀ allele฀distributions฀of฀TNF- α,฀IFN- γ,฀and฀IL-10฀ polymorphisms฀in฀the฀three฀groups฀of฀patients฀ analyzed.฀In฀particular,฀bipolar฀II฀patients฀were฀ characterized฀by฀an฀absence฀of฀adenine฀(A)฀ high฀producer฀allele฀of฀TNF- α฀( P<.001)฀and฀a฀ lower฀percentage฀of฀TT฀high฀producer฀genotype฀ of฀IFN-γ฀(P<.001);฀bipolar฀I฀individuals฀showed฀ reduced฀percentage฀of฀AA฀low฀producer฀geno-