title: Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn's Disease and Ulcerative Colitis.
abstract: BACKGROUND
  Recent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/TH17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD).
  
  
  METHODS
  We conducted a prospective study of U.S. women enrolled in the Nurses' Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case-control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in TH17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naïve and memory T cells, differentiated with TGFβ1 or TH17 conditions.
  
  
  RESULTS
  Among a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend= 0.005) but not sodium (Ptrend= 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend= 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (Pinteraction= 0.004 and 0.01, respectively).In vitro, potassium enhanced the expression of Foxp3 in both naïve and memory CD4+ T cellsviaactivating Smad2/3 and inhibiting Smad7 in TH17 cells.
  
  
  CONCLUSIONS
  Dietary potassium is inversely associated with risk of CD with bothin vitroand gene-environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway.
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Hamed
authors.initials: H
authors.lastname: Khalili
authors.affiliation: Translational Health Science and Technology Institute, NCR Biotech Science Cluster , Faridabad , India.
authors.forename: Sakshi
authors.initials: S
authors.lastname: Malik
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Ashwin N
authors.initials: AN
authors.lastname: Ananthakrishnan
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Garber
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Higuchi
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine , Baltimore, MD , USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Peloquin
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Richter
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: Kathleen O
authors.initials: KO
authors.lastname: Stewart
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Curhan
authors.affiliation: Translational Health Science and Technology Institute, NCR Biotech Science Cluster , Faridabad , India.
authors.forename: Amit
authors.initials: A
authors.lastname: Awasthi
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Yajnik
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
keywords: Crohn’s disease; Nurses’ Health Study; TH17 pathway; dietary potassium; immune tolerance; inflammatory bowel disease; ulcerative colitis