Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Transl Med. 2023 Jun 7;21(1):370. 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.
观察性研究和传统的孟德尔随机化（MR）研究都没有得出确凿的证据来支持ω-3 脂肪酸与 2 型糖尿病之间的关联。我们旨在评估ω-3 脂肪酸对 2 型糖尿病（T2DM）的因果效应，以及连接两者的不同中间表型。
使用来自英国生物库（UK Biobank）的最新全基因组关联研究（GWAS）中ω-3 脂肪酸的遗传工具（N=114999）和欧洲血统的大规模 T2DM GWAS（62892 例病例和 596424 例对照）中的结果数据，进行双样本 MR 分析。使用 MR-Clust 确定影响 T2DM 的ω-3 脂肪酸的聚类遗传工具。两步 MR 分析用于确定连接ω-3 脂肪酸与 T2DM 的潜在中间表型（例如血糖特征）。
单变量 MR 显示 ω-3 脂肪酸对 T2DM 的影响存在异质性。使用 MR-Clust 鉴定出至少两种 ω-3 脂肪酸与 T2DM 之间的多效性作用。对于包含七个工具的簇 1，增加 ω-3 脂肪酸可降低 T2DM 风险（OR：0.52，95%CI 0.45-0.59），并降低 HOMA-IR（β=-0.13，SE=0.05，P=0.02）。相反，在簇 2 中使用 10 个工具进行 MR 分析表明，增加 ω-3 脂肪酸会增加 T2DM 风险（OR：1.10；95%CI 1.06-1.15），并降低 HOMA-B（β=-0.04，SE=0.01，P=4.52×10）。两步 MR 分析表明，在簇 1 中，增加 ω-3 脂肪酸水平可通过降低 HOMA-IR 来降低 T2DM 风险，而在簇 2 中则通过降低 HOMA-B 来增加 T2DM 风险。
本研究提供了证据支持ω-3 脂肪酸对 T2DM 风险的两种不同的多效性作用，这可能受到不同基因簇的影响，这可以部分解释为 ω-3 脂肪酸对胰岛素抵抗和β细胞功能障碍的不同作用。在未来的遗传和临床研究中，需要仔细考虑 ω-3 脂肪酸变体的多效性特征及其与 T2DM 的复杂关系。
