title: 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.
authors.affiliation: 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. g.mazzoccoli@operapadrepio.it
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.forename: Orazio
authors.initials: O
authors.lastname: Palmieri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Corritore
authors.forename: Tiziana
authors.initials: T
authors.lastname: Latiano
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bossa
authors.forename: Daniela
authors.initials: D
authors.lastname: Scimeca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biscaglia
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Valvano
authors.forename: Renata
authors.initials: R
authors.lastname: D'Incà
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cucchiara
authors.forename: Laura
authors.initials: L
authors.lastname: Stronati
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
authors.forename: Angelo
authors.initials: A
authors.lastname: Andriulli
authors.forename: Anna
authors.initials: A
authors.lastname: Latiano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: C512644:PER3 protein, human; D056950:Period Circadian Proteins