Antioxidants, Minerals and Vitamins in Relation to CD and UC

Abstract and Introduction

Abstract

Background: Evidence for antioxidants, minerals and vitamins in relation to the risk of Crohn's disease (CD) and ulcerative colitis (UC) is limited and inconsistent. This mendelian randomization (MR) study aimed to examine the causal associations of circulating levels of antioxidants, minerals and vitamins with CD and UC.

Methods: Single-nucleotide polymorphisms associated with antioxidants (beta-carotene, lycopene and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc and selenium), and vitamins (folate, vitamins A, B6, B12, C, D, E and K1) were employed as instrumental variables. Genetic associations with CD and UC were extracted from the UK Biobank, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium. The inverse variance weighted method and sensitivity analyses were performed.

Results: Genetically predicted higher lycopene (OR = 0.94, 95% CI: 0.91–0.97), vitamins D (OR = 0.65, 95% CI: 0.54–0.79) and K1 (OR = 0.93, 95% CI: 0.90–0.97) levels were inversely associated with CD risk, whereas genetically predicted higher magnesium (OR = 1.53, 95% CI: 1.23–1.90) levels were positively associated with CD risk. Higher levels of genetically predicted lycopene (OR = 0.91, 95% CI: 0.88–0.95), phosphorus (OR = 0.69, 95% CI: 0.58–0.82), selenium (OR = 0.91, 95% CI: 0.85–0.97), zinc (OR = 0.91, 95% CI: 0.89–0.94), folate (OR = 0.71, 95% CI: 0.56–0.92) and vitamin E (OR = 0.78, 95% CI: 0.69–0.88) were associated with reduced UC risk, whereas genetically predicted high levels of calcium (OR = 1.46, 95% CI: 1.22–1.76) and magnesium (OR = 1.24, 95% CI: 1.03–1.49) were associated with increased risk of UC.

Conclusions: Our study provided evidence that circulating levels of antioxidants, minerals and vitamins might be causally linked to the development of IBD.

Introduction

Inflammatory bowel disease (IBD), including Crohn's Disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract with a rising incidence in populations.^[1] Although the precise aetiology of IBD remains unclear, accumulating evidence from observational studies suggests that dietary nutrients especially antioxidants, minerals and vitamins contribute to the pathogenesis of IBD.^[2,3] Unfortunately, published research on the associations between dietary nutrients, especially antioxidants, minerals and vitamins and IBD is scarce and inconclusive. An umbrella review of meta-analyses found that high vitamin D levels decreased the risk of CD and UC;^[4] however, a randomised controlled trial (RCT) examining the effect of supplemental vitamin D did not show a significant clinical benefit.^[5] Large prospective cohort studies have reported that dietary zinc intake was inversely associated with incident CD,^[6,7] whereas in a small RCT, zinc supplementation seemed to play little part in restraining inflammation in patients with IBD.^[8] Potential explanations for these inconsistent results may relate to the substantial biases (residual confounding and reverse causation) in observational studies as well as low adherence to treatment, low treatment doses, short trial duration and low statistical power in RCTs. The causal role of antioxidants, minerals and vitamins in the development of CD or UC remains unclear.

Mendelian randomization (MR) utilises genetic variants as instruments to make inferences in causal relationships between risk factors and disease outcomes.^[9] As germline genetic variants are randomly allocated at meiosis, MR design minimises confounding and is not influenced by environmental or self-adopted factors and therefore strengthens causal inference. Construction of a validated MR association relies on three key assumptions: (1) genetic variant is associated with the exposure; (2) the genetic variant is not related to confounding; (3) the genetic variant has no effect on outcome directly.^[10] A previous MR study including 25,042 IBD cases indicated no association of genetically predicted vitamin D levels with CD or UC risk.^[11] Still, the MR associations of antioxidants, minerals and vitamins with CD or UC risk have not been systematically evaluated. Here, we conducted an MR investigation to comprehensively explore the causal associations of antioxidants, minerals and vitamins with CD and UC.

Authors and Disclosures

Jie Chen^1–3, Xixian Ruan¹, Shuai Yuan⁴, Minzi Deng¹, Han Zhang³, Jing Sun³, Lili Yu³, Jack Satsangi⁵, Susanna C. Larsson^4,6, Evropi Therdoratou^7,8, Xiaoyan Wang¹ and Xue Li³

¹Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
²Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China
³Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁴Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
⁵Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK
⁶Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
⁷Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
⁸Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK

Correspondence
Xue Li, School of Public Health, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Email: xueli157@zju.edu.cn
Xiaoyan Wang, Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China. Email: wangxiaoyan@csu.edu.cn

Jie Chen and Xixian Ruan are joint first authors.

Xiaoyan Wang and Xue Li are joint corresponding authors.

Author contributions
All authors made critical revisions of the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript. Jie Chen (Conceptualization: Equal; Methodology: Equal; Formal analysis: Equal; Data curation: Equal; and Writing – original draft: Equal). Xixian Ruan (Conceptualization: Equal; Methodology: Equal; Formal analysis: Equal; and Writing – original draft: Equal). Shuai Yuan (Conceptualization: Supporting; Methodology: Supporting; Writing – review & editing: Supporting). Minzi Deng (Conceptualization: Supporting; Writing – review & editing: Supporting). Han Zhang (Conceptualization: Supporting; Writing – review & editing: Supporting). Jing Sun (Conceptualization: Supporting; Writing – review & editing: Supporting). Lili Yu (Conceptualization: Supporting; Writing – review & editing: Supporting). Jack Satsangi (Conceptualization: Supporting; Methodology: Supporting; Writing – review & editing: Supporting). Susanna C. Larsson (Conceptualization: Equal; Methodology: Equal; Data curation: Equal; and Writing – review & editing: Leading). Evropi Therdoratou (Conceptualization: Equal; Methodology: Equal; Writing – review & editing: Leading). Xiaoyan Wang (Conceptualization: Leading; Data curation: Equal; and Funding acquisition: Leading; Writing – review & editing: Equal). Xue Li (Conceptualization: Equal; Data curation: Equal; Funding acquisition: Equal; and Writing – review & editing: Leading). All authors approved the final version of the manuscript.

Conflict of Interest
All authors declare no competing interest.

Funding information
CRUK Career Development Fellowship, Grant/Award Number: C31250/A22804; National Natural Science Foundation of China, Grant/Award Number: 81970494; Natural Science Fund for Distinguished Young Scholars of Zhejiang Province, Grant/Award Number: LR22H260001; Swedish Cancer Society; Swedish Heart Lung Foundation, Grant/Award Number: 20210351; Swedish Research Council, Grant/Award Number: 2019–00977; Key Project of Research and Development Plan of Hunan Province, Grant/Award Number: 2019SK2041
XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001). ET is supported by a CRUK Career Development Fellowship (C31250/A22804). SCL acknowledges research funding from the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20,210,351), the Swedish Research Council (Vetenskapsrådet, 2019–00977) and the Swedish Cancer Society (Cancerfonden). XYW is supported by National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province (2019SK2041).