Association Between the ACE Insertion/Deletion Polymorphism and Risk of Lower-Limb Amputation in Patients With Long-Standing Type 1 Diabetes
RESEARCH DESIGN AND METHODS. ACE I/D genotype and plasma ACE were assessed in three prospective cohorts of participants with type 1 diabetes. LLA was defined as minor (below the ankle amputation consisting of at least 1-ray metatarsal resection) or major (transtibial or transfemoral) amputation. Linear, logistic and Cox regression models were computed to evaluate the likelihood of prevalent and incident LLA by ACE genotype (XD [ID or ID] versus II) and plasma ACE, after adjusting for confounders.
RESULTS. Among 1301 participants (male 54%, age 41±13 years), 90 (6.9%) participants had a baseline history of LLA. Baseline LLA was more prevalent in XD (7.4%) than in II genotype (4.5%): OR 2.17 (95%CI, 1.03–4.60). Incident LLA occurred in 53 individuals during 14-year follow-up. It was higher in XD versus II carriers: HR 3.26 (1.16–13.67). This association was driven by excess risk of minor, but not major, LLA. The D-allele was associated with increased prevalent LLA at the end of follow-up (OR 2.48 [1.33–4.65]). LLA was associated with higher ACE levels in II (449 [360–539] versus 354 [286–423] ng/ml), but not in XD carriers (512 [454–570] versus 537 [488–586]).
CONCLUSIONS. This is the first report of an independent association between ACE D-allele and excess LLA risk, mainly minor amputations, in patients with type 1 diabetes.