ACE protein, human; Peptidyl-Dipeptidase A; Adult; Amputation; Genotype; Humans; Lower Extremity/surgery; Male; Middle Aged; Polymorphism, Genetic/genetics; Prospective Studies; Diabetes Mellitus, Type 1/genetics; Diabetes Mellitus, Type 1/surgery; Peptidyl-Dipeptidase A/genetics; Diabetes Mellitus, Type 1; Lower Extremity; Polymorphism, Genetic; Internal Medicine; Endocrinology, Diabetes and Metabolism; Advanced and Specialized Nursing
Abstract :
[en] OBJECTIVE: 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.
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 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.
RESULTS: 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.
CONCLUSIONS: 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.
Mohammedi, Kamel ; Department of Endocrinology, Diabetes and Nutrition, Bordeaux University Hospital, Hôpital Haut-Lévêque, Pessac, France ; Faculty of Medicine, University of Bordeaux, Bordeaux, France ; Biology of Cardiovascular Diseases, INSERM U1034, Pessac, France
Abouleka, Yawa; Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, Paris, France ; Service d'Endocrinologie Diabétologie Nutrition, Hôpital Bichat, AP-HP, Paris, France
Carpentier, Charlyne; Service d'Endocrinologie Diabétologie Nutrition, CHU d'Angers, Angers, France
Potier, Louis; Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, Paris, France ; Service d'Endocrinologie Diabétologie Nutrition, Hôpital Bichat, AP-HP, Paris, France
Dubois, Severine; Service d'Endocrinologie Diabétologie Nutrition, CHU d'Angers, Angers, France
Foussard, Ninon; Department of Endocrinology, Diabetes and Nutrition, Bordeaux University Hospital, Hôpital Haut-Lévêque, Pessac, France ; Faculty of Medicine, University of Bordeaux, Bordeaux, France
Rigalleau, Vincent; Department of Endocrinology, Diabetes and Nutrition, Bordeaux University Hospital, Hôpital Haut-Lévêque, Pessac, France ; Faculty of Medicine, University of Bordeaux, Bordeaux, France
Gautier, Jean-François ; Université de Liège - ULiège > Département des sciences cliniques > Médecine interne générale ; Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, Paris, France ; Service de Diabétologie et d'Endocrinologie, Hôpital Lariboisière, AP-HP, Université de Paris, Paris, France
Gourdy, Pierre; Service d'Endocrinologie Diabétologie Nutrition, CHU de Toulouse, Toulouse, France ; Institut des Maladies Métaboliques et Cardiovasculaires, UMR1297 INSERM/UPS, Université Toulouse 3, Toulouse, France
Charpentier, Guillaume; 10Center for Study and Research for Improvement of the Treatment of Diabetes, Bioparc-Génopole Évry-Corbeil, Évry, France
Roussel, Ronan; Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, Paris, France ; Service d'Endocrinologie Diabétologie Nutrition, Hôpital Bichat, AP-HP, Paris, France
SCHEEN, André ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques
Bauduceau, Bernard; 12Service d'Endocrinologie, Hôpital Bégin, Saint Mandé, France
Hadjadj, Samy; 13Institut du Thorax, INSERM, CNRS, Université de Nantes, CHU Nantes, Nantes, France
Alhenc-Gelas, François; Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, Paris, France
Marre, Michel; Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, Paris, France ; 14Clinique Ambroise Paré, Neuilly-sur-Seine, France
Velho, Gilberto; Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, Paris, France
Association Between the ACE Insertion/Deletion Polymorphism and Risk of Lower-Limb Amputation in Patients With Long-Standing Type 1 Diabetes.
Publication date :
2022
Journal title :
Diabetes Care
ISSN :
0149-5992
eISSN :
1935-5548
Publisher :
American Diabetes Association Inc., United States
Volume :
45
Issue :
2
Pages :
407-415
Peer reviewed :
Peer Reviewed verified by ORBi
Funding text :
Acknowledgments. The authors thank all the patients who participated to this study as well as their physicians. The list of contributors is available in the Supplementary Material. Funding. Y.A. was supported by a grant from the Association Diabète Risque Vasculaire. Duality of Interest. K.M. reportspersonal fees or nonfinancial support from Novo Nordisk, Sanofi, AstraZeneca, Eli Lilly, Abbott, and Boehringer Ingelheim. P.G. reports grants or personal fees from Abbott, Amgen, AstraZe-neca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Mundipharma, Novo Nordisk, Sanofi, and Servier. A.S. has received lecturer/advisor fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, and Servier. R.R. reports research grants from Sanofi, Novo Nordisk, and Dia-bnext and consulting and speakers’ bureau fees (compensation donated to the nonprofit AP-HP Foundation for research) from Sanofi, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Mundipharma, Janssen, AstraZeneca, MSD, Medtronic, and Abbott. S.H. reports personal fees and nonfinancial support from AstraZe-neca, grants and personal fees from Bayer, personal fees from Boehringer Ingelheim, grants from Dinno Santé, personal fees from Eli Lilly, nonfinancial support from LVL Medi-phar, personal fees and nonfinancial support from MSD, personal fees from Novartis, grants from Pierre Fabre Santé, personal fees and nonfinancial support from Sanofi, personal fees and nonfinancial support from Servier, and personal fees from Valbiotis. M.M. is a consultant for Novo Nordisk Algerian subsidiary and has received personal fees from Novo Nordisk, Merck Sharp & Dohme, and Eli Lilly. No other potential conflicts of interest relevant to this article were reported. Author Contributions. K.M., M.M., and G.V. designed the study, researched data, and wrote the manuscript. Y.A., C.C., L.P., S.D., N.F., V.R., J.-F.G., P.G., G.C., R.R., A.S., B.B., F.A.-G., and S.H. researched data, contributed to the discussion, and reviewed/edited the manuscript. All authors approved the current version of the manuscript. K.M. and G.V. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses.
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