HbA1c as an Independent Predictor of Peripheral Artery Disease: Nonlinear Threshold and Causal Evidence from NHANES and Mendelian Randomization

BackgroundPeripheral artery disease (PAD) is a major contributor to cardiovascular morbidity and mortality, yet reliable biomarkers for early detection remain limited. Glycated hemoglobin (HbA1c) reflects long-term glycemia, but its relationship with PAD in the general population remains incompletely understood.MethodsWe analyzed 6284 adults aged ≥40 years from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). PAD was defined as an ankle-brachial index ≤0.90. Weighted logistic regression, restricted cubic spline, and threshold models evaluated associations between HbA1c and PAD. To further examine causality, a two-sample Mendelian randomization (MR) using genome-wide association data on HbA1c (n = 389,889) and PAD (7098 cases, 206541 controls) was conducted.ResultsIn NHANES, each 1% increment in HbA1c was linked to a higher likelihood of PAD (fully adjusted OR 1.18, 95% CI 1.04-1.34). Participants in the highest HbA1c tertile had more than a twofold greater risk compared with those in the lowest (OR 2.30, 95% CI 1.68-3.15). Restricted cubic spline analysis revealed a nonlinear relationship with a threshold at 6.11%, below which PAD risk rose steeply. In MR analysis, genetically predicted HbA1c was positively associated with PAD risk, showing that genetically predicted HbA1c was positively associated with PAD (IVW OR 1.23, 95% CI 1.10-1.37, p = 0.0002), with consistent results across sensitivity analyses.ConclusionElevated HbA1c is independently and causally linked to PAD risk, with a nonlinear dose-response pattern. These findings support HbA1c as a potential tool for identifying individuals at higher PAD risk.