Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study

Background —Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms (SNPs) of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-proADM) are associated with cardiovascular diseases. Methods and Results —We investigated the sources of variability of ADM gene expression and plasma MR-proADM concentrations in the general population, and their relationship to markers of atherosclerosis. MR-proADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness (IMT) and arterial rigidity (reflection index [RI] and stiffness index [SI]). In a sub-sample of 1372 individuals, ADM gene expression was assessed as part of a transcriptomic study of circulating monocytes. Non-genetic factors explained 45.8% and 7.5% of MR-proADM and ADM expression variability, respectively. ADM expression correlated to plasma C-reactive protein, interleukin-receptor 1A and myeloperoxidase, while MR-proADM levels correlated to C-terminal pro-endothelin-1, creatinine and N-terminal pro-B-type natriuretic peptide. Genome-wide association study of ADM expression and MR-proADM levels both identified a single locus encompassing the ADM gene. ADM expression was associated to a single SNP rs11042717 (p=2.36 10-12) while MR-proADM was associated to 2 SNPs with additive effects, rs2957692 (p=1.54 10-13) and rs2957717 (p=4.24 10-8). RI was independently associated to rs11042717 (p<10-4) and ADM expression (p=0.0002) but not to MR-proADM. Weaker associations were observed for SI. IMT was not related to ADM SNPs or expression. Conclusions —These results support an involvement of the ADM gene in the modulation of peripheral vascular tone.