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Higuchi, Leslie

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Higuchi

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Leslie

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Higuchi, Leslie
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    Physical activity and risk of inflammatory bowel disease: prospective study from the Nurses’ Health Study cohorts
    (BMJ Publishing Group Ltd., 2013) Khalili, Hamed; Ananthakrishnan, Ashwin; Konijeti, Gauree G; Liao, Xiaomei; Higuchi, Leslie; Fuchs, Charles; Spiegelman, Donna; Richter, James; Korzenik, Joshua; Chan, Andrew
    Objective: To examine the association between physical activity and risk of ulcerative colitis and Crohn’s disease. Design: Prospective cohort study. Setting: Nurses’ Health Study and Nurses’ Health Study II. Participants: 194 711 women enrolled in the Nurses’ Health Study and Nurses’ Health Study II who provided data on physical activity and other risk factors every two to four years since 1984 in the Nurses’ Health Study and 1989 in the Nurses’ Health Study II and followed up through 2010. Main outcome measure Incident ulcerative colitis and Crohn’s disease. Results: During 3 421 972 person years of follow-up, we documented 284 cases of Crohn’s disease and 363 cases of ulcerative colitis. The risk of Crohn’s disease was inversely associated with physical activity (P for trend 0.02). Compared with women in the lowest fifth of physical activity, the multivariate adjusted hazard ratio of Crohn’s disease among women in the highest fifth of physical activity was 0.64 (95% confidence interval 0.44 to 0.94). Active women with at least 27 metabolic equivalent task (MET) hours per week of physical activity had a 44% reduction (hazard ratio 0.56, 95% confidence interval 0.37 to 0.84) in risk of developing Crohn’s disease compared with sedentary women with <3 MET h/wk. Physical activity was not associated with risk of ulcerative colitis (P for trend 0.46). The absolute risk of ulcerative colitis and Crohn’s disease among women in the highest fifth of physical activity was 8 and 6 events per 100 000 person years compared with 11 and 16 events per 100 000 person years among women in the lowest fifth of physical activity, respectively. Age, smoking, body mass index, and cohort did not significantly modify the association between physical activity and risk of ulcerative colitis or Crohn’s disease (all P for interaction >0.35). Conclusion: In two large prospective cohorts of US women, physical activity was inversely associated with risk of Crohn’s disease but not of ulcerative colitis.
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    Endogenous Levels of Circulating Androgens and Risk of Crohn's Disease and Ulcerative Colitis Among Women: A Nested Case–Control Study from the Nurses' Health Study Cohorts
    (Lippincott Williams & Wilkins, 2015) Khalili, Hamed; Ananthakrishnan, Ashwin; Konijeti, Gauree G.; Higuchi, Leslie; Fuchs, Charles; Richter, James; Tworoger, Shelley; Hankinson, Susan; Chan, Andrew
    Background: Androgens, which are known to be altered by exogenous hormone use, have recently been linked to alterations of the gut microbiome and mucosal immune function. No study has evaluated the association between circulating levels of androgens and risk of Crohn's disease (CD) and ulcerative colitis (UC). Methods: We conducted a nested case–control study of women enrolled in the Nurses' Health Study and Nurses' Health Study II who provided a blood specimen. Cases of CD and UC were each matched to 2 controls. Prediagnosis plasma levels of dehydroepiandrosterone sulfate, testosterone, and sex hormone–binding globulin were measured. We examined the association of each analyte with risk of CD or UC using conditional logistic regression models. Results: Compared with women in the lowest quintile of testosterone, the multivariable-adjusted odds ratios for CD were 0.86 (95% confidence interval, 0.39–1.90) for women in the second quintile, 0.49 (95% confidence interval, 0.21–1.15) for the third quartile, 0.22 (0.08–0.65) for the fourth quintile, and 0.39 (95% confidence interval, 0.16–0.99) for the highest quintile (Plinear trend = 0.004). In contrast, we did not observe a consistent association between prediagnostic testosterone and risk of UC (Plinear trend = 0.84). We also did not observe any association between plasma levels of sex hormone–binding globulin or dehydroepiandrosterone sulfate and risk of UC or CD (all Plinear trends > 0.10). Conclusions: Among women, prediagnostic circulating testosterone is associated with a lower risk of CD but not UC. Further studies to understand the biological mechanisms by which endogenous androgens may mediate the etiopathogenesis of CD are warranted.
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    Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn’s Disease and Ulcerative Colitis
    (Frontiers Media S.A., 2016) Khalili, Hamed; Malik, Sakshi; Ananthakrishnan, Ashwin; Garber, John; Higuchi, Leslie; Joshi, Amit; Peloquin, Joanna; Richter, James; Stewart, Kathleen O.; Curhan, Gary; Awasthi, Amit; Yajnik, Vijay; Chan, Andrew
    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.