Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study

Chunyan Hu, Yulin Zhou, Xueyan Wu, Xiaojing Jia, Yuanyue Zhu, Ruizhi Zheng, Shuangyuan Wang, Lin Lin, Hongyan Qi, Hong Lin, Mian Li, Tiange Wang, Zhiyun Zhao, Min Xu, Yu Xu, Yuhong Chen, Guang Ning, Maria-Carolina Borges, Weiqing Wang, Jie ZhengYufang Bi, Jieli Lu

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)


BACKGROUND: Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two.

METHODS: Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM.

RESULTS: Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45-0.59), and decreased HOMA-IR (β = - 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06-1.15), and decreased HOMA-B (β = - 0.04, SE = 0.01, P = 4.52 × 10-5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2.

CONCLUSIONS: This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

Original languageEnglish
Pages (from-to)370
JournalJournal of Translational Medicine
Issue number1
Publication statusPublished - 7 Jun 2023

Bibliographical note

© 2023. The Author(s).

Structured keywords

  • Bristol Population Health Science Institute


  • Humans
  • Diabetes Mellitus, Type 2/drug therapy
  • Mendelian Randomization Analysis
  • Genome-Wide Association Study
  • Fatty Acids, Omega-3/pharmacology
  • Phenotype
  • Polymorphism, Single Nucleotide/genetics


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