Association Study of a Polymorphism in Clock Gene PERIOD3 and Risk of Inflammatory Bowel Disease

Abstract

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

ACKNOWLEDGMENTS

The authors wish to thank all the patients and families who participated in this study. The following physicians of the SIGENP* and adult gastrointestinal units contributed to the study by providing DNA samples and clinical information of their patients: *Ancona: C. Catassi, S. Nobile; *Bari: V. Rutigliano, D. De Venuto; *Foggia: A. Campanozzi; *Messina: G. Vieni, C. Sferlazzas; Milano: G. Bianchi Porro, M. Vecchi, S. Saibeni; Napoli: G. Riegler, *Napoli: E. Berni Canani, A. M. Staiano; Padova: G. C. Sturniolo; *Padova: G. Guariso; *Palermo: S. Accomando; *Parma: G. L. de Angelis; *Pescara: G. Lombardi; *Reggio Calabria: C. Romano; *Roma: O. Borrelli, C. Bascietto; *Firenze: P. Lionetti; *Genova: A. Barabino; *S. Giovanni Rotondo: M. D'Altilia, A. Marseglia.

Declaration of Interest: This study was supported by a grant from the Italian Ministry of Health through Department of Medical Sciences, Division of Gastroenterology (RC1202GA38) and Division of Internal Medicine and Chronobiology Unit (RC1203ME46), IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza,” Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy.

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.