Journal Article

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

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

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Beta cells / Biobanks / Biomedical and Life Sciences / Biomedicine / Cardiovascular disease / Care and treatment / Diabetes / Diabetes mellitus (non-insulin dependent) / Diagnosis / Disease prevention / Estimates / Fatty acids / Gene clusters / Genetic aspects / Genetic epidemiology / Genome-wide association studies / Genomes / Glucose / Glucose metabolism / Health aspects / Insulin resistance / Lipids / Medicine/Public Health / Mendelian randomization / Nutrition & metabolism / Observational studies / Omega-3 fatty acids / Phenotypes / Pleiotropic effects / Pleiotropy / Triglycerides / Type 2 diabetes