Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Hu C

PROVIDER: S-EPMC10249205 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Hu Chunyan C Zhou Yulin Y Wu Xueyan X Jia Xiaojing X Zhu Yuanyue Y Zheng Ruizhi R Wang Shuangyuan S Lin Lin L Qi Hongyan H Lin Hong H Li Mian M Wang Tiange T Zhao Zhiyun Z Xu Min M Xu Yu Y Chen Yuhong Y Ning Guang G Borges Maria-Carolina MC Wang Weiqing W Zheng Jie J Bi Yufang Y Lu Jieli J

Journal of translational medicine 20230607 1

<h4>Background</h4>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.<h4>Methods</h4>Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty a ...[more]

PMID: 37286992

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Project description:BackgroundOmega-3 and omega-6 may be protective factors for cholelithiasis. However, this relationship has not yet been demonstrated clearly. Therefore, we attempted to identify these causal relationships.Materials and methodsThe omega-3/6 fatty acid discovery dataset was obtained from UK Biobank and contained 114,999 individuals. The validation set was derived from an independent genome-wide association study (GWAS) and contained 13,544 individuals. The cholelithiasis dataset was derived from FinnGen and contained 19,023 cases and 195,144 controls. The inverse variance weighting (IVW) method was used as the main method of analysis in this study. Multiple methods of analysis were also used in the repeated methods, including the MR-Egger, weighted median, MR-pleiotropic residual sum (MR-PRESSO), outliers, and maximum likelihood methods. In addition, we used multiple sensitivity analyses to identify the potential pleiotropy.ResultIn the discovery stage, the results of the random effect IVW analysis showed that higher omega-3 levels were correlated inversely with the risk of cholelithiasis (β = -0.22, 95% CI [-0.32 to -0.12], P = 1.49 × 10-5). When the replication analysis was performed using another set of instrumental variables (IVs), the causal relationship between omega-3 fatty acids and cholelithiasis remained stable (β = -0.42, 95% CI [-0.66 to -0.18], P = 5.49 × 10-4), except for the results obtained using the MR-Egger method, which were not significant. The results of the IVW approach showed that each SD increase in omega-6 levels was associated negatively with the risk of cholelithiasis, both in the discovery (β = -0.21, 95% CI [-0.35 to -0.06], P = 4.37 × 10-3) and the validation phases (β = -0.21, 95% CI [-0.40 to -0.02], P = 3.44 × 10-2).ConclusionThe results of our MR study suggest that omega-3/6 is associated with cholelithiasis risk. Attention to the risk of cholelithiasis in individuals with low serum omega-3/6 levels is necessary.

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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