Association Study of a Polymorphism in Clock Gene PERIOD3 and Risk of Inflammatory Bowel Disease Gianluigi Mazzoccoli, 1 Orazio Palmieri, 2 Giuseppe Corritore, 2 Tiziana Latiano, 2 Fabrizio Bossa, 2 Daniela Scimeca, 2 Giuseppe Biscaglia, 2 Maria Rosa Valvano, 2 Renata D’Incà, 3 Salvatore Cucchiara, 4 Laura Stronati, 5 Vito Annese, 6 Angelo Andriulli, 2 and Anna Latiano 2 1 Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy, 2 Department of Medical Sciences, Research Laboratory and Division of Gastroenterology, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy, 3 Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy, 4 Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, “La Sapienza” University, Rome, Italy, 5 Department of Radiobiology and Human Health, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Rome, Italy, 6 Division of Gastroenterology, Careggi Hospital, University of Florence, Florence, Italy Altered body rhythmicity and deregulated clock gene expression may cause circadian disruption, which can lead to immune dysregulation and chronic inflammatory diseases. PERIOD3 (PER3) polymorphisms have been associated with circadian disruption and changed secretion of cytokines involved in chronic inflammation. Crohn’s disease (CD) and ulcerative colitis (UC) are multifactorial diseases resulting from complex interaction among environmental/ microbial factors and the intestinal immune system, triggering an abnormal immune response in genetically susceptible individuals. We evaluated the influence of a polymorphism of the clock gene PER3 on susceptibility and behavior of these inflammatory bowel diseases. The rs2797685 variant of the PER3 gene was assessed in 1082 CD and 972 UC patients, 754 of whom had been diagnosed <18 yrs of age, and 1311 unrelated healthy controls. Allele and genotype frequencies of rs2797685 were significantly increased in both CD ( p = 1.6 × 10 -4 , odds ratio [OR] = 1.38, 95% confidence interval [CI]: 1.17–1.63) and UC ( p = .012, OR = 1.25, 95% CI: 1.05–1.48) patients. Difference between frequency distributions remained statistically significant after stratifying the cohort according to age at diagnosis for CD, but not for UC. Statistically significant association was found between PER3 polymorphism and use of immunosuppressive drugs in pediatric CD patients ( p < .001) and with stricturing and fistulizing disease behavior in adult CD patients ( p = .031). In conclusion, results of this association study suggest a possible role of PER3 polymorphism in determining susceptibility to CD and UC and phenotypic characteristics of CD. In particular, the rs2797685 variant of the PER3 gene is associated with a more aggressive form of CD, highlighted by higher use of immunosuppressants and more frequent stricturing and fistulizing disease behaviors, as well as early onset of CD. This is a descriptive study, and functional data are needed to prove a causal relationship; nonetheless, involvement of the clock gene machinery in the susceptibility and the behavior of inflammatory bowel diseases may suggest new pathophysiological mechanisms and new therapeutic approaches. (Author correspondence: g.mazzoccoli@ operapadrepio.it) Keywords: Circadian rhythmicity, Clock gene, Crohn’s disease, PER3, Ulcerative colitis INTRODUCTION Many biological processes and functions in humans display time-related variations, and when the periodic variations or rhythms have a frequency of 1 cycle/24 ± 4 h they are termed circadian (from the latin circa, approximately, and dies, 24-h day) (Dibner et al., 2010; Lemmer, 2009). Circadian rhythms in mammals are driven by the circadian timing system, comprising a central pacemaker, i.e., master oscillator located in the hypothalamic suprachiasmatic nuclei (SCN), which are Gianluigi Mazzoccoli and Orazio Palmieri contributed equally to this study. Address correspondence to Gianluigi Mazzoccoli, MD, Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza,” 71013 San Giovanni Rotondo (FG), Italy. Tel.: + 39 0882 835321; Email: g.mazzoccoli@operapadrepio.it Submitted January 9, 2012, Returned for revision February 23, 2012, Accepted May 25, 2012 Chronobiology International, Early Online: 1–10, (2012) Copyright © Informa Healthcare USA, Inc. ISSN 0742-0528 print/1525-6073 online DOI: 10.3109/07420528.2012.705935  Chronobiol Int Downloaded from informahealthcare.com by 2.198.25.234 on 08/10/12 For personal use only.