Five phenotypes exhibit significant causal associations with DFU: seven show suggestive causal associations. Body mass index (BMI) is a significant risk factor (OR 1.24, 95% CI 1.09 to 1.42 per kg/m2). This correlation remains stable between both sexes, with males (OR 1.43, 95% CI 1.20 to 1.71) having a slightly higher risk than females (OR 1.34, 95% CI 1.16 to 1.54). Creatine kinase (OR 3.05, 95% CI 1.06 to 8.78 per SD unit) and smoking initiation are suggestive risk factors. Compared with individuals who have never smoked, those with a smoking history have a 4.30 times higher risk of DFU (95% CI 1.02 to 18.21).

Years of schooling are the only significant protective factor (OR 0.15, 95% CI 0.05 to 0.49 per SD unit). Total protein (TP) has an adjusted p value close to the statistical threshold (padjusted=0.051) and is a protective factor (OR 0.80, 95% CI 0.69 to 0.93 per g/L). Other suggestive protective factors include mean corpuscular volume (MCV) (OR 0.91, 95% CI 0.84 to 0.98 per fL), mean corpuscular hemoglobin (MCH) (OR 0.78, 95% CI 0.63 to 0.96 per pg), 25-hydroxyvitamin D (25OHD) (OR 0.97, 95% CI 0.94 to 0.99 per nmol/L), and platelet (OR 0.92, 95% CI 0.85 to 0.99 per 109/L).

Nine phenotypes exhibit significant causal associations with DPN, and 15 show suggestive causal associations. BMI is also a significant risk factor (OR 1.12, 95% CI 1.07 to 1.18). The risk is slightly higher in males (OR 1.17, 95% CI 1.10 to 1.26) compared with females (OR 1.15, 95% CI 1.09 to 1.22). Height (OR 1.04, 95% CI 1.03 to 1.06 per cm) and Aspartate aminotransferase (AST) (OR 1.003, 95% CI 1.001 to 1.004 per IU/L) are also significant. All glycemic traits, except 2-hour glucose, show causal associations with DPN. HbA1c (OR 3.32, 95% CI 1.76 to 6.26 per SD unit) and BMI-adjusted fasting insulin (FI) levels (OR 2.24, 95% CI 1.31 to 3.82 per SD unit) are significant. Fasting glucose (FG) is a suggestive risk factor, with BMI-adjusted FG (OR 2.00, 95% CI 1.12 to 3.57) showing a slightly higher risk compared with FI (OR 1.99, 95% CI 1.11 to 3.58). Years of schooling (OR 0.46, 95% CI 0.30 to 0.70) are also a significant protective factor for DPN, while the hardest math class (OR 0.60, 95% CI 0.37 to 0.99 per SD unit) shows suggestive protective effects.

Thirty phenotypes exhibit significant causal associations with DPAD: three show suggestive causal associations. BMI is also significant for DPAD (OR 1.10, 95% CI 1.08 to 1.12). The risk is slightly higher in males (OR 1.11, 95% CI 1.09 to 1.14) than in females (OR 1.10, 95% CI 1.08 to 1.12). Hypertension (OR 1.003, 95% CI 1.001 to 1.004), coronary artery disease (OR 1.82, 95% CI 1.70 to 1.95), and atrial fibrillation (OR 1.06, 95% CI 1.02 to 1.11) are significant risk factors.

All blood pressure traits are the risk factors for DPAD. Among them, pulse pressure is the most significant (OR 1.06, 95% CI 1.04 to 1.07 per mm Hg), while systolic blood pressure (OR 1.03, 95% CI 1.02 to 1.04) and diastolic blood pressure (OR 1.03, 95% CI 1.01 to 1.04) exhibited similar effects.

Smoking traits are the risk factors for DPAD. Compared with never smokers, smoking initiation was associated with a 2.95 times increased risk (95% CI 2.43 to 3.59), and for ex-smokers, current smokers have a 3.40 times higher risk (95% CI 2.25 to 5.13). Every 1 SD unit increase in daily smoking is associated with a 2.40 times higher risk (95% CI 2.03 to 2.82). Moreover, starting smoking at an older age is associated with a more significant reduction in DPAD risk (OR 0.68, 95% CI 0.59 to 0.78 per SD unit).

All glycemic traits are significant, with FI (OR 4.11, 95% CI 2.34 to 7.22) having the most significant effect, followed by BMI-adjusted FI (OR 1.94, 95% CI 1.57 to 2.40), HbA1c (OR 1.83, 95% CI 1.44 to 2.33), 2-hour glucose (OR 1.51, 95% CI 1.18 to 1.93), and BMI-adjusted FG (OR 1.34, 95% CI 1.08 to 1.67).

Uric acid (OR 1.13, 95% CI 1.04 to 1.23 per mg/dL), gamma-glutamyl transferase (OR 1.004, 95% CI 1.002 to 1.01 per IU/L), mean corpuscular hemoglobin concentration (OR 1.28, 95% CI 1.13 to 1.45 per percent), waist circumference (WC) (OR 1.006, 95% CI 1.003 to 1.008 per cm), female WC (OR 1.37, 95% CI 1.23 to 1.53 per SD unit), waist to hip ratio (WHR) (OR 141.67, 95% CI 27.89 to 719.46 per fold), and female WHR (OR 1.50, 95% CI 1.36 to 1.66 per SD unit) are also significant risk factors for DPAD.

Protective factors for DPAD include years of schooling (OR 0.54, 95% CI 0.47 to 0.62), hardest mathematics class (OR 0.69, 95% CI 0.57 to 0.82), and BMI-adjusted insulin sensitivity index (OR 0.49, 95% CI 0.38 to 0.64 per SD unit).

The sensitivity analysis detected heterogeneity in a few exposures related to the DPN in FINN, specifically from European origin BMI, bipolar affective disorder, serum uric acid, lymphocyte count, and unadjusted FI levels. No significant level of horizontal pleiotropy was detected in others. Some exposure factors showed a degree of heterogeneity across different outcomes, but the Weight median (WM) results indicated their directions were consistent with the IVW results. The MR-PRESSO analysis revealed that outliers existed for certain exposure factors across all outcomes. However, when these outliers were eliminated, the results remained consistent with the primary outcomes, with no significant changes in statistical significance or effect direction. After removing the outliers, the CI of the estimated effect was slightly smaller than the primary results. The leave-one-out analysis did not identify any IV that could significantly change the results. The results of the sensitivity analysis, along with the leave-one-out plot, funnel plots, and scatter plots, can be found in online supplemental files S1–S3.