Adrenomedullin and Arterial Stiffness: Integrative Approach Combining Monocyte ADM Expression, Plasma MR-Pro-ADM, and Genome-Wide Association Study

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d16663542e225">Background</h5> <p id="P1">Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the <i>ADM</i> gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d16663542e233">Methods and Results</h5> <p id="P2">We investigated the sources of variability of <i>ADM</i> gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection index and stiffness index). In a subsample of 1372 individuals, <i>ADM</i> gene expression was assessed as part of a transcriptomic study of circulating monocytes. Nongenetic factors explained 45.8% and 7.5% of MR-pro-ADM and <i>ADM</i> expression variability, respectively. <i>ADM</i> expression correlated with plasma C-reactive protein, interleukin-receptor 1A, and myeloperoxidase, whereas MR-pro-ADM levels correlated with C-terminal proendothelin-1, creatinine, and N-terminal pro–B-type natriuretic peptide. Genome-wide association study of <i>ADM</i> expression and MR-pro-ADM levels both identified a single locus encompassing the <i>ADM</i> gene. <i>ADM</i> expression was associated with 1 single nucleotide polymorphism rs11042717 ( <i>P</i>=2.36×10 ⁻¹²), whereas MR-pro-ADM was associated with 2 single nucleotide polymorphisms with additive effects, rs2957692 ( <i>P</i>=1.54×10 ⁻¹³) and rs2957717 ( <i>P</i>=4.24×10 ⁻⁸). Reflection index was independently associated with rs11042717 ( <i>P</i>&lt;10 ⁻⁴) and <i>ADM</i> expression ( <i>P</i>=0.0002) but not with MR-pro-ADM. Weaker associations were observed for stiffness index. Intima-media thickness was not related to <i>ADM</i> single nucleotide polymorphisms or expression. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d16663542e295">Conclusions</h5> <p id="P3">These results support an involvement of the <i>ADM</i> gene in the modulation of peripheral vascular tone. </p> </div>