Genetically Predicted Higher Levels of Caffeic Acid Are Protective Against Ulcerative Colitis: A Comprehensive Metabolome Analysis
Author:
Naito Takeo1ORCID, Osaka Ryuya1, Kakuta Yoichi1ORCID, Kawai Yosuke2, Khor Seik-Soon23, Umeno Junji4, Tokunaga Katsushi25, , Ishibashi-Ueda Hantsue, Tomita Tsutomu, Noguchi Michio, Takahashi Ayako, Goto Yu-ichi, Yoshida Sumiko, Hattori Kotaro, Matsumura Ryo, Iida Aritoshi, Maruoka Yutaka, Gatanaga Hiroyuki, Sugiyama Masaya, Suzuki Satoshi, Miyo Kengo, Matsubara Yoichi, Umezawa Akihiro, Hata Kenichiro, Kaname Tadashi, Ozaki Kouichi, Tokuda Haruhiko, Watanabe Hiroshi, Niida Shumpei, Noiri Eisei, Kitajima Koji, Omae Yosuke, Miyahara Reiko, Shimanuki Hideyuki, Kawai Yosuke, Tokunaga Katsushi, Nagai Hiroshi1, Shimoyama Yusuke1, Moroi Rintaro1, Shiga Hisashi1ORCID, Nagasaki Masao67, Kinouchi Yoshitaka8, Masamune Atsushi1
Affiliation:
1. Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan 2. Genome Medical Science Project, National Center for Global Health and Medicine , Tokyo , Japan 3. Centre for Environmental Life Sciences Engineering, Nanyang Technological University Singapore , Singapore 4. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 5. Central Biobank, National Center Biobank Network , Tokyo , Japan 6. Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University , Fukuoka , Japan 7. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University , Kyoto , Japan 8. Student Health Care Center, Institute for Excellence in Higher Education, Tohoku University , Sendai , Japan
Abstract
Abstract
Background
It is crucial to pinpoint the metabolites that cause Crohn’s disease (CD) and ulcerative colitis (UC) to comprehend their pathogenesis and identify possible targets for therapy. To achieve this goal, we performed the first metabolome-wide Mendelian randomization (MR) study of Japanese patients with CD and UC.
Methods
As exposure datasets, genetic instruments with blood-circulating metabolites were obtained from the Tohoku Medical Megabank Organization, which includes 204 metabolites from the genome-wide association study data of 7843 Japanese individuals. As outcome datasets, we enrolled Japanese patients with CD (n = 1803), Japanese patients with UC (n = 1992), and healthy controls (n = 2022). The main analysis utilized the inverse variance–weighted method, while stability of the findings was evaluated through sensitivity analyses.
Results
After single nucleotide polymorphism (SNP) filtering, 169 SNPs for 45 metabolites were available for MR. Genetically predicted elevated circulating trans-glutaconic acid and tryptophan were associated with a lower CD risk (odds ratio [OR], 0.68; P = 5.95 × 10−3; and OR, 0.64; P = 1.90 × 10−2, respectively). Genetically predicted elevated caffeic acid was associated with a lower UC risk (OR, 0.67; P = 4.2 × 10−4), which remained significant after multiple testing correction. We identified a causal link between UC and 3-hydroxybutyrate (OR, 2.21; P = 1.41 × 10−2), trans-glutaconic acid (OR, 0.72; P = 1.77 × 10−2), and 2-hydroxyvaleric acid (OR, 1.31; P = 4.23 × 10−2). There was no evidence of pleiotropy or reverse causal effects for these candidate metabolites.
Conclusions
In our metabolome-wide MR study, we discovered a notable protective effect of caffeic acid against UC.
Funder
Japan Society for the Promotion of Science KAKENHI Japan Science and Technology Agency NBDC
Publisher
Oxford University Press (OUP)
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