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Plasma adrenomedullin, allelic variations in the ADM gene, and risk for lower-limb amputation in people with type 2 diabetes

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posted on 18.05.2022, 14:53 authored by Louis Potier, Kamel Mohammedi, Pierre-Jean Saulnier, Frédéric Fumeron, Jean-Michel Halimi, Nicolas Venteclef, Michel Marre, Samy Hadjadj, Ronan Roussel, Gilberto Velho

Objective: Patients with diabetes have an increased risk for lower-limb amputation (LLA) but biomarkers to assess risk of LLA are lacking. Adrenomedullin (ADM) is a vasodilator peptide that also plays a role on fluid and electrolyte homeostasis in the kidney, increasing natriuresis and diuresis. ADM was shown to be associated with cardiovascular and renal events in diabetes, but it was not investigated in terms of LLA risk. We investigated the hypothesis that ADM is associated with LLA in people with type 2 diabetes.

Research Design and Methods: We studied 4375 participants of DIABHYCAR and SURDIAGENE cohorts (men 68%, mean age 66 years, mean duration of diabetes 12 years, median follow-up 5.3 years). Plasma MR-proADM (a surrogate for ADM) was measured by immunofluorescence. Five SNPs in the ADM gene region were genotyped.

Results: LLA requirement during follow-up by increasing tertiles of plasma MR-proADM distribution was 1.0% (T1), 2.3% (T2) and 4.4% (T3) (p<0.0001). In Cox multivariate analysis, adjusted hazard ratio (95%CI) for LLA was 4.40 (2.30–8.88; p<0.0001) for T3 vs. T1. Moreover, MR-proADM significantly improved indices for risk stratification of LLA. Four SNPs were associated with plasma MR-proADM concentration at baseline and with LLA during follow-up. Alleles associated with higher MR-proADM were associated with increased LLA risk.

Conclusions: We observed associations of plasma MR-proADM with LLA and of ADM SNPs with plasma MR-proADM and with LLA in people with type 2 diabetes. This pattern of Mendelian randomization supports the causality of the association of ADM with LLA.

Funding

The original DIABHYCAR trial and cohort recruitment was supported by grants from Sanofi-Aventis (Paris), the French Ministry of Health (PHRC – Angers 1996) and the "Association Française des Diabétiques" (AFD; Research Grant 2004). The SURDIAGENE study was supported by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique [PHRC]-Poitiers 2004) and Association Française des Diabetiques (AFD) (Research Grant 2003). The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

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