Analysis of dietary vitamin C intake levels and the risk of hyperuricemia and gout based on cross-sectional studies and bi-directional Mendelian randomisation

Background: Vitamin C, a common antioxidant, may be useful for treating hyperuricemia and gout. The aim of this study was to investigate the risk association between dietary vitamin C intake and hyperuricemia/gout and to test for causality using the bi-directional Mendelian randomisation method. Methods: Cross sectional studies were selected from the National Health and Nutrition Examination Survey from 2007 to 2018 to assess the association between dietary vitamin C intake and the risk of hyperuricemia/gout, according to multivariate logistic regression modelling. Bi directional Mendelian randomisation studies were conducted using genetic data from large scale genome wide association surveys of supplemental vitamin C, pharmacological vitamin C, and ascorbic acid intake and hyperuricemia/gout; these aimed to infer causal relationships between vitamin C and hyperuricemia/gout. Inverse variance weighting was used as the primary method of Mendelian randomisation analysis. A series of sensitivity analyses were used to assess multiplicity. Results: The cross-sectional study included 17.52% and 82.48% patients with and without hyperuricemia, respectively, as well as 2.67% and 97.33% patients with and without gout, respectively. In the model correcting for all covariates, the association between vitamin C intake and the risk of hyperuricemia/gout was stable, and the risk of hyperuricemia was generally lower in patients who consumed >111.75 mg vitamin C than in other patients when comparing three models with different moderators. Restricted cubic spline scores indicated that vitamin C intake recommendations of 75 to 525 mg and 75 to 225 mg were effective for targeting hyperuricemia and gout, respectively. In inverse variance weighting in the Mendelian randomisation analysis, the amount of vitamin C absorbed was negatively associated with hyperuricemia (OR = 0.985, 95% CI = 0.973 to 0.997, p = 0.015), and supplemental vitamin C was negatively associated with gout (OR = 0.857, 95% CI = 0.797 to 0.921, p < 0.001); sensitivity analysis yielded consistent results. Reverse Mendelian randomisation analysis showed that vitamin C had no reverse causal relationship with hyperuricemia and gout. Conclusion: We hypothesise that a dietary vitamin C intake of 75 to 525 mg or 75 to 225 mg may reduce the risk of hyperuricemia and gout, respectively. Further research with larger samples is required to confirm this. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Natural Science Foundation of China (81960863 and 82160901), Construction Project of Yunnan Provincial Fund for Medical Research Center (202102AA310006), Construction Project of National Traditional Chinese Medicine Clinical Research Base (2018 No. 131), Construction Project for the Focal Branch of National Traditional Chinese Medicine (2023 No. 85), The Expert Workstation of Zhangxuan in Yunnan Province (202305AF150175), Funding of Yunnan Applied Basic Research Projects-Union Applied Basic Research Projects-Union Foundation (2019FF002[-082], 2019FF002[-031], 202101AZ070001-072 and 202101AZ070001-074), and Yunnan Provincial Traditional Chinese Medicine Discipline Reserve Talent Training Project (2021 No. 01). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at: https://www.cdc.gov/nchs/nhanes/index.htm and https://gwas.mrcieu.ac.uk/. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. All data produced in the present work are contained in the manuscript. All data produced are available online at.