Background: Globally, 1 in 11 adults has diabetes mellitus, and most of these cases are type 2 diabetes (T2D). The risk of T2D is influenced by many factors, including diet. The synthesis of long-chain n-6 polyunsaturated fatty acids (LC n-6 PUFA) has been posited as a risk factor for T2D; however, its causal role is uncertain. Aim: To test the causal effect of LC n-6 PUFA synthesis on insulin resistance and transgenerational T2D risk in a large cohort of men and women. Methods: Two-sample mendelian randomization (MR) was conducted to evaluate the effect of low or high levels of LC n-6 PUFA synthesis on glycemia and development of T2D in the UK Biobank (n = 463,010) and Meta-Analysis of Glucose- and Insulin-Related Traits Consortium (MAGIC; n = 5,130) cohorts. The increased likelihood of a predisposition to low or high LC n-6 PUFA synthesis and the risk of T2D was also investigated using the participants’ siblings and parents. In MR-Base, 4 genetic variants associated with LC n-6 PUFA synthesis were found (p < 10–8). After pruning, 1 variant (rs174547) on the FADS1 gene was retained. Results: Lower LC n-6 PUFA synthesis and abundance (per % unit decrease) are associated with small reductions in the insulin disposition index (–0.038 ± 0.012 mM–1; p = 0.002) within MAGIC. In the UK Biobank, we report negligible effects of low n-6 PUFA synthesis on the odds of T2D (OR <1%; p < 0.05). Additionally, reduced LC n-6 PUFA synthesis does not appear to be a contributor to familial T2D risk. No significant association was observed between LC n-6 PUFA synthesis and BMI. Conclusion: In a primarily white European population, LC n-6 PUFA synthesis is not a major contributor to T2D risk.

中文翻译：

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研究长链 n-6 多不饱和脂肪酸合成与 2 型糖尿病风险之间的因果关系：孟德尔随机化分析

背景：在全球范围内，每 11 名成人中就有 1 人患有糖尿病，其中大部分病例为 2 型糖尿病 (T2D)。T2D 的风险受许多因素的影响，包括饮食。长链 n-6 多不饱和脂肪酸 (LC n-6 PUFA) 的合成已被认为是 T2D 的危险因素；然而，它的因果作用是不确定的。目的：在一大群男性和女性中测试 LC n-6 PUFA 合成对胰岛素抵抗和跨代 T2D 风险的因果影响。方法：在英国生物银行 (n = 463,010) 和葡萄糖的荟萃分析中，进行了两样本孟德尔随机化 (MR) 以评估低或高水平的 LC n-6 PUFA 合成对血糖和 T2D 发展的影响。和胰岛素相关性状联盟（MAGIC；n = 5,130）队列。还使用参与者的兄弟姐妹和父母研究了低或高 LC n-6 PUFA 合成倾向的增加的可能性以及 T2D 的风险。在 MR-Base 中，发现了 4 个与 LC n-6 PUFA 合成相关的遗传变异（p < 10-8）。修剪后，保留了 FADS1 基因上的 1 个变体 (rs174547)。结果：较低的 LC n-6 PUFA 合成和丰度（每 % 单位减少）与 MAGIC 内胰岛素处置指数的小幅减少（–0.038 ± 0.012 mM–1；p = 0.002）有关。在英国生物银行，我们报告了低 n-6 PUFA 合成对 T2D 几率的影响可以忽略不计（OR <1%；p < 0.05）。此外，减少的 LC n-6 PUFA 合成似乎不是家族性 T2D 风险的因素。未观察到 LC n-6 PUFA 合成与 BMI 之间的显着关联。结论：