Heredity and cardiometabolic risk

Abstract

Objectives The neuropeptide Y2 G-protein-coupled receptor (NPY2R) relays signals from PYY or neuropeptide Y toward satiety and control of body mass. Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R promoter genetic variation in more than 10 000 human participants indicate its involvement in control of obesity and BMI. Here we searched for genetic variation across the human NPY2R locus and probed its functional effects, especially in the proximal promoter. Methods and results Twin pair studies indicated substantial heritability for multiple cardiometabolic traits, including BMI, SBP, DBP, and PYY, an endogenous agonist at NPY2R. Systematic polymorphism discovery by resequencing across NPY2R uncovered 21 genetic variants, 10 of which were common [minor allele frequency (MAF) >5%], creating one to two linkage disequilibrium blocks in multiple biogeographic ancestries. In vivo, NPY2R haplotypes were associated with both BMI (P =3.75E–04) and PYY (P =4.01E–06). Computational approaches revealed that proximal promoter variants G-1606A, C-599T, and A-224G disrupt predicted IRF1 (A>G), FOXI1 (T>C), and SNAI1 (A>G) response elements. In neuroendocrine cells transfected with NPY2R promoter/luciferase reporter plasmids, all three variants and their resulting haplotypes influenced transcription (G-1606A, P <2.97E–06; C-599T, P <1.17E–06; A-224G, P <2.04E–06), and transcription was differentially augmented or impaired by coexpression of either the cognate full-length transcription factors or their specific siRNAs at each site. Endogenous expression of transcripts for NPY2R, IRF1, and SNAI1 was documented in neuroendocrine cells, and the NPY2R mRNA was differentially expressed in two neuroendocrine tissues (adrenal gland, brainstem) of a rodent model of hypertension and the metabolic syndrome, the spontaneously hypertensive rat. Conclusion We conclude that common genetic variation in the proximal NPY2R promoter influences transcription factor binding so as to alter gene expression in neuroendocrine cells, and consequently cardiometabolic traits in humans. These results unveil a novel control point, whereby cis-acting genetic variation contributes to control of complex cardiometabolic traits, and point to new transcriptional strategies for intervention into neuropeptide actions and their cardiometabolic consequences.

Neuroendocrinological and Epigenetic Mechanisms Subserving Autonomic Imbalance and HPA Dysfunction in the Metabolic Syndrome

“…Expression of NPY1R in adipose tissue was observed relating to the MetS components weight and insulin resistance (Sitticharoon et al, 2013 ). NPY2R (4q31) participates in modification of cardiometabolic traits (Wei et al, 2013 ), with its 21 known SNPs. Haplotypes of the proximal promoter variants G-1606A, C-599T, and A-224G disrupted predicted dependent genes, influenced the transcription of the interferon regulation factor related to IL-6, and the hepatocyte nuclear factor.…”

Neuropeptide Y-mediated sex- and afferent-specific neurotransmissions contribute to sexual dimorphism of baroreflex afferent function

“…Recent results have indicated that naturally occurring genetic variation at the Y 1 R locus has implications for heritable autonomic control of the circulation and hypertension, suggesting novel pathophysiological links among the Y 1 R locus, autonomic activity, and BP [ 8 ]. Y 2 R expression is upregulated in spontaneously hypertensive rats [ 9 ] and endogenous expression of Y 2 R is also documented in neuroendocrine cells and neuroendocrine tissues including the brainstem of a rodent model of hypertension [ 10 ].…”

Neuroendocrine Effects on the Risk of Metabolic Syndrome in Children

“…Indeed, NPY is primarily produced in the arcuate nucleus, with its orexigenic effects manifesting in the paraventricular nucleus, thereby inducing hunger, lowering energy expenditure, and contributing to obesity [ 11 ]. Some of the NPY receptors mediate neuroendocrine effects and, among these, NPY1R expression in fat cells is associated with the development of MetS by promoting insulin resistance and fat mass accumulation, whereas some variants of NPY2R may influence cardiometabolic traits [ 11 , 79 , 80 , 81 ]. In addition, the gene NPY2R (4q31) plays a crucial role in an animal model of MetS, causing abdominal fat deposition and angiogenesis in adipose tissue in response to sympathetic nerve stimulation in response to social or environmental stress [ 11 , 82 ].…”