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Backgrounds & aims: Plant-based diets may target multiple pathways in gout pathogenesis (uric acid reduction and anti-inflammation) while improving gout associated cardiometabolic comorbidities. We aim to prospectively examine the relationship between a vegetarian diet and gout, and to explore if this relationship is independent of hyperuricemia. Methods: We followed 4903 participants in the Tzu Chi Health Study (Cohort1, recruited in 2007e2009) and 9032 participants in the Tzu Chi Vegetarian Study (Cohort2, recruited in 2005) until end of 2014. Baseline serum uric acid was measured in Cohort1. Vegetarian status was assessed through a diet questionnaire that includes dietary habits and a food frequency questionnaire. Incidence of gout was ascertained by linkage to the National Health Insurance Database. Hazard Ratio of gout in vegetarians versus nonvegetarians was assessed by Cox regression, adjusted for age, sex, lifestyle and metabolic risk factors. Hyperuricemia was additionally adjusted in Cohort1. Results: In Cohort1, lacto-ovo vegetarians had the lowest uric acid concentration, followed by vegans, then nonvegetarians (men: 6.05, 6.19, 6.32 mg/dL, respectively; women: 4.92, 4.96, 5.11 mg/dL, respectively); 65 gout cases occurred in the 29,673 person-years of follow-up; vegetarians experienced a lower risk of gout (without adjustment for hyperuricemia: HR: 0.33; 95% CI: 0.14, 0.79; with adjustment for hyperuricemia: HR: 0.40; 95% CI: 0.17, 0.97). In Cohort2, 161 gout cases occurred in the 83,019 personyears follow-up, and vegetarians also experienced a lower risk of gout (HR: 0.61; 95% CI: 0.41, 0.88). Conclusion: Taiwanese vegetarian diet is associated with lower risk of gout. This protective association may be independent of baseline hyperuricemia.

T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP-seq and de novo motif analysis reveals NF-κB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell-derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link.