Association Between the ACE Insertion/Deletion Polymorphism and Risk of Lower-Limb Amputation in Patients With Long-Standing Type 1 Diabetes

• Published in: Diabetes care Vol. 45; no. 2; pp. 407 - 415
• Main Authors: Mohammedi, Kamel, Abouleka, Yawa, Carpentier, Charlyne, Potier, Louis, Dubois, Severine, Foussard, Ninon, Rigalleau, Vincent, Gautier, Jean-François, Gourdy, Pierre, Charpentier, Guillaume, Roussel, Ronan, Scheen, André, Bauduceau, Bernard, Hadjadj, Samy, Alhenc-Gelas, François, Marre, Michel, Velho, Gilberto
• Format: Journal Article Web Resource
• Language: English
• Published: United States American Diabetes Association 01-02-2022; American Diabetes Association Inc
• Subjects: ACE protein, human; Adult; Advanced and Specialized Nursing; Alleles; Amputation; Ankle; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - surgery; Endocrinologie, métabolisme & nutrition; Endocrinology, Diabetes and Metabolism; Endocrinology, metabolism & nutrition; Gene deletion; Gene polymorphism; Genotype; Genotype & phenotype; Human health sciences; Humans; Insertion; Internal Medicine; Life Sciences; Lower Extremity; Lower Extremity - surgery; Male; Metatarsus; Middle Aged; Peptidyl-Dipeptidase A; Peptidyl-Dipeptidase A - genetics; Pharmacie, pharmacologie & toxicologie; Pharmacy, pharmacology & toxicology; Polymorphism; Polymorphism, Genetic; Polymorphism, Genetic - genetics; Prospective Studies; Regression analysis; Regression models; Research design; Risk; Santé publique et épidémiologie; Sciences de la santé humaine
• ISSN: 0149-5992; 1935-5548; 1935-5548; 0149-5992
• DOI: 10.2337/dc21-0973

The ACE insertion/deletion (I/D) polymorphism has been widely studied in people with diabetes, albeit not with regard to lower-limb amputation (LLA). We examined associations among this polymorphism, plasma ACE concentration, and LLA in people with type 1 diabetes.
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 one 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] vs. II) and plasma ACE, after adjusting for confounders.
Among 1,301 participants (male 54%, age 41 ± 13 years), 90 (6.9%) had a baseline history of LLA. Baseline LLA was more prevalent in XD (7.4%) than in II genotype (4.5%, odds ratio [OR] 2.17 [95 %CI 1.03-4.60]). Incident LLA occurred in 53 individuals during the 14-year follow-up and was higher in XD versus II carriers (hazard ratio 3.26 [95% CI 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 mean (95% CI) ACE levels in II (449 [360, 539] vs. 354 [286, 423] ng/mL), but not XD (512 [454, 570] vs. 537 [488, 586]), carriers.
This report is the first of an independent association between ACE D allele and excess LLA risk, mainly minor amputations, in patients with type 1 diabetes.