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OBJECTIVE -- Charcot neuroarthropathy is a disabling complication of diabetes. Although its pathogenesis remains unknown, we suppose that genetics may play a relevant role. RESEARCH DESIGN AND METHODS-- We performed a case-control study with 59 subjects with diabetic Charcot neuroarthropathy (Ch group), 41 with diabetic neuropathy without Charcot neuroarthropathy (ND group), and 103 healthy control subjects (H group) to evaluate the impact of two single nucleotide polymorphisms (SNPs) of the osteoprotegerin gene (G1181C and T245G) on the risk of Charcot neuroarthropathy. RESULTS-- Regarding the SNPs of G1181C, we found a significant linkage between the G allele and Charcot neuroarthropathy (Ch vs. ND, odds ratio [OR] 2.32 [95% CI 1.3-4.1], P = 0.006; Ch vs. H, 2.10 [1.3-3.3], P = 0.002; and ND vs. H, 0.90 [0.7-1.9], P = 0.452); similarly, we found a linkage with the G allele of T245G (Ch vs. ND, 6.25 [2.2-19.7], P < 0.001; Ch vs. H, 3.56 [1.9-6.7], P = 0.001; and ND vs. H, 0.54 [0.6-5.7], P = 0.304), supporting a protective role for the allele C and T, respectively. For this reason we investigated the frequency of the protective double homozygosis CC + TT (7% in Ch) that was significantly lower in Ch compared with H (0.18 [0.06-0.5], P = 0.002) and with ND (0.17 [0.05-0.58], P = 0.006), whereas there was no difference between H and ND (1.05 [0.43-2.0], P = 0.468). In a multivariate logistic backward regression model, only weight and the lack of CC and TT genotypes were independently associated with the presence of Charcot neuroarthropathy. CONCLUSIONS-- This is the first study that shows an association between genetic regulation of bone remodeling and Charcot neuroarthropathy. [ABSTRACT FROM AUTHOR]