DataSheet_1_Polyunsaturated fatty acids and diabetic microvascular complications: a Mendelian randomization study.docx

BackgroundObservational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications.
MethodsWe identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications.
ResultsThe study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47–0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62–0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed.
ConclusionsOur MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.

研究背景：观察性研究与临床试验均表明，多不饱和脂肪酸（polyunsaturated fatty acids, PUFAs）或可对糖尿病微血管并发症起到保护作用。然而，由于不同研究结果存在分歧，二者之间的因果关联仍不明确。本研究采用孟德尔随机化（Mendelian randomization, MR）方法，评估多不饱和脂肪酸对糖尿病微血管并发症的因果影响。
研究方法：我们基于英国生物银行（UK Biobank）数据集，筛选出多不饱和脂肪酸（包括ω-3与ω-6脂肪酸）的工具变量。糖尿病微血管并发症的结局数据来源于芬根研究（FinnGen Study）。本研究分析涵盖了1型与2型糖尿病的微血管结局，具体包括糖尿病神经病变（diabetic neuropathy, DN）、糖尿病视网膜病变（diabetic retinopathy, DR）以及糖尿病肾病（diabetic kidney disease, DKD）。同时开展反向孟德尔随机化分析，以探究糖尿病微血管并发症对多不饱和脂肪酸的影响。通过敏感性分析验证研究结果的稳健性。最后，采用多变量孟德尔随机化（multivariable MR, MVMR）分析，以明确多不饱和脂肪酸是否对糖尿病微血管并发症存在直接影响。
研究结果：本研究发现，遗传预测的ω-6脂肪酸水平升高可显著降低2型糖尿病患者的糖尿病神经病变风险（比值比（odds ratio, OR）=0.62，95%置信区间（confidence interval, CI）：0.47~0.82，P=0.001）。同时提示ω-6脂肪酸对2型糖尿病患者的糖尿病视网膜病变具有保护作用（OR=0.75，95%CI：0.62~0.92，P=0.005）。多变量孟德尔随机化分析证实，在校正潜在混杂因素后，上述结果依然稳定。未观察到ω-6脂肪酸对2型糖尿病患者的糖尿病肾病，以及1型糖尿病患者的任一微血管并发症存在显著影响。与之相反，ω-3脂肪酸与本次评估的任一糖尿病微血管并发症均未发现显著因果关联。
研究结论：本孟德尔随机化研究揭示了ω-6脂肪酸与2型糖尿病患者的部分糖尿病微血管并发症之间存在因果关联，可为糖尿病微血管并发症的后续机制研究与临床探索提供全新视角。