Neuropeptide Y (NPY)

Abstract

Objectives This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells. Background The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15. Methods Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population. Results Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇−880Δ (2-bp TG/—, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h2) stress traits: higher NPY secretion (h2 = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇−880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele −880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter −880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same −880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes. Conclusions We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇−880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.

Understanding resilience

“…One recent study found that two NPY haplotypes represented by three single nucleotide polymorphisms (SNPs) correlated with increased susceptibility to anxiety disorders after childhood adversity, and suggested that such behavioral effects can be mediated by altered NPY expression and subsequently dampened HPA-axis responsiveness under the influence of the genetic variation (Donner et al, 2012). Other studies also demonstrated that NPY release was substantially mediated by genetic variations in the NPY locus, especially in the promoter region, and that lower haplotype-driven NPY expression predicted weakened resilient response to stress (Zhou et al, 2008; Zhang et al, 2012). …”

Psychosocial factors and hematopoietic stem cell transplantation: Potential biobehavioral pathways

“…Structural genomics approaches offer the opportunity for identification of polymorphisms that confer both physical and psychological susceptibility; genetic polymorphisms in signaling molecules and their receptors adversely impact stress adaptation responses in non-cancer populations and may have implications for HCT recipients (Agrawal et al, 2012; Zhang et al, 2012). …”

Effect of Dipeptidyl Peptidase 4 Inhibition on Arterial Blood Pressure Is Context Dependent

“…Some studies show a correlation between blood pressure and NPY levels 43 and demonstrate higher NPY levels in patients with essential hypertension 44 . Recent evidence suggests an association of polymorphisms in the NPY promoter with hypertension 15, 45 . Thus it is likely that some patients have NPY-dependent elevations in blood pressure, and DPP4 inhibitors would likely increase blood pressure in such patients.…”

“…For example, DPP4 inhibitors decrease the metabolism of endogenous glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, such as the incretin hormone GLP-1(7–36)NH 2 , and GLP-1R agonists are antihypertensive 14 . DPP4 inhibitors also impair the metabolism of endogenous Y 1 receptor (Y 1 R) agonists, such as neuropeptide Y 1–36 (NPY 1–36 ), and Y 1 R agonists may be pro-hypertensive 15 . Therefore, the net effects of DPP4 inhibitors on arterial blood pressure may well depend on the prevailing balance of a large number of peptides that affect the kidneys, vasculature, sympathoadrenal axis and brain; and this balance may in turn depend on such factors as genetics, physiological state, method of blood pressure measurement, diet, co-administration of antihypertensive drugs and time frame of blood pressure measurement.…”