Genetic Evidence for Adiposity-Related Susceptibility and Heel BMD-Proxied Skeletal Resilience in Charcot Foot: A Two-Sample Mendelian Randomization Study.

Abstract

BackgroundCharcot neuro-osteoarthropathy (CNO) is a limb-threatening diabetic foot complication involving neuropathy, repetitive trauma, inflammation, and bone remodeling. Obesity is common in CNO, but observational interpretation is limited by confounding and reverse causation.MethodsWe performed two-sample MR using GWAS summary statistics. The primary outcome was FinnGen R12 Charcot foot. BMI was prespecified as primary; glycemic traits, lipids, metabolic traits, and heel bone mineral density (BMD), a systemic proxy for skeletal strength, were secondary or comparator exposures. Instruments were genome-wide significant and European LD-clumped.ResultsPer standardized BMI increment, higher BMI was strongly associated with Charcot foot (odds ratio [OR], 3.36; 95% CI, 2.30-4.92; P = 4.01 × 10^-10); 1 standardized BMI unit is approximately 4.7 to 4.8 kg/m² in large European cohorts. BMI was nominally associated with diabetic neuropathy (OR, 1.21; 95% CI, 1.04-1.42; P = 0.016). Fasting glucose was suggestive (OR, 2.35; 95% CI, 1.14-4.81; P = 0.020). Higher heel BMD was associated with lower Charcot foot risk (OR, 0.75; 95% CI, 0.59-0.96; P = 0.021).ConclusionsGenetically proxied higher BMI was strongly associated with Charcot foot risk; fasting glucose and heel BMD-proxied skeletal findings were suggestive. These findings support considering adiposity in long-term risk recognition alongside neuropathy surveillance, foot protection, and offloading.