Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn’s Disease and Ulcerative Colitis

Frontiers in Immunology

Dec 2016

DOI: 10.3389/fimmu.2016.00554

Citations:48

Influential Citations:5

Observational Studies (Human)

Enhanced Details

Methods

Two large prospective cohorts of US women (Nurses' Health Study and NHSII). NHS baseline: ~121,700 participants aged 30–55; NHSII baseline: ~116,686 participants aged 25–42. Combined analyses included 194,711 women with 3,220,247 person-years of follow-up (CD: 273 cases; UC: 335 cases). Diet assessed by a 161-item semi-quantitative FFQ; Crohn’s disease and ulcerative colitis confirmed via medical records. A nested case–control analysis within cohorts evaluated interaction between six TH17 pathway SNPs and dietary potassium on CD/UC risk (169 CD cases with 740 controls; 202 UC cases with 740 controls). An in vitro component used PBMCs from 25 healthy volunteers to study potassium effects on naive and memory CD4+ T cells under TH17/TGF-β conditions.

Results

In 194,711 women followed through 2010–2011, 273 CD and 335 UC cases were documented. Dietary potassium intake was inversely associated with CD risk (highest vs lowest quintile HR 0.62; 95% CI 0.40–0.95; Ptrend 0.005). No significant association with UC (Ptrend 0.08). Across the full cohort, each 200 mg/day increase in potassium linked to ~7% lower CD risk (OR 0.93; 95% CI 0.86–1.00); for UC, OR 0.98 (0.91–1.05). TH17 SNP rs7657746 (IL21) modified potassium-CD association: GG genotype showed higher CD risk with increased potassium (OR 1.58; 95% CI 1.15–2.16), while GA (OR 0.96; 95% CI 0.86–1.07) and AA (OR 0.90; 95% CI 0.82–0.98) genotypes showed neutral or protective effects. UC interactions followed a similar pattern (Pinteraction = 0.01). In vitro, potassium enhanced Foxp3 expression in naive and memory CD4+ T cells by activating Smad2/3 and inhibiting Smad7, and amplified TGF-β–induced Foxp3+ Tregs even in TH17 conditions, without affecting viability. Authors conclude that dietary potassium is inversely associated with CD risk, with gene–environment and in vitro data supporting a potential role in regulating immune tolerance through Tregs and TH17 pathways; further research is needed to confirm causality and explore clinical implications.

Limitations

FFQ-based dietary assessment introduces measurement error; limited sample size for gene–environment interaction analyses; observational design cannot establish causality; study population largely white female nurses, limiting generalizability; no adjustment for multiple testing in interaction analyses; in vitro findings may not fully reflect in vivo biology.

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 cells via activating Smad2/3 and inhibiting Smad7 in TH17 cells. Conclusion Dietary potassium is inversely associated with risk of CD with both in vitro and gene–environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway. show less