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

• Published in: Journal of translational medicine Vol. 21; no. 1; p. 370
• Main Authors: Hu, Chunyan, Zhou, Yulin, Wu, Xueyan, Jia, Xiaojing, Zhu, Yuanyue, Zheng, Ruizhi, Wang, Shuangyuan, Lin, Lin, Qi, Hongyan, Lin, Hong, Li, Mian, Wang, Tiange, Zhao, Zhiyun, Xu, Min, Xu, Yu, Chen, Yuhong, Ning, Guang, Borges, Maria-Carolina, Wang, Weiqing, Zheng, Jie, Bi, Yufang, Lu, Jieli
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07.06.2023; BioMed Central; BMC
• Subjects: Analysis; Beta cells; Biobanks; Cardiovascular disease; Care and treatment; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diagnosis; Disease prevention; Estimates; Fatty acids; Fatty Acids, Omega-3 - pharmacology; Fatty Acids, Omega-3 - therapeutic use; Gene clusters; Genetic aspects; Genetic epidemiology; Genome-wide association studies; Genome-Wide Association Study; Genomes; Glucose; Glucose metabolism; Health aspects; Humans; Insulin resistance; Lipids; Mendelian randomization; Mendelian Randomization Analysis; Observational studies; Omega-3 fatty acids; Phenotype; Phenotypes; Pleiotropic effects; Pleiotropy; Polymorphism, Single Nucleotide - genetics; Triglycerides; Type 2 diabetes; United Kingdom; United Kingdom > UK; Type 2 diabetes; Glucose metabolism; Mendelian randomization; Genetic epidemiology; Pleiotropic effects; Omega-3 fatty acids
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-023-04202-7

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. 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. 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 ). 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. 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.