Neuropeptide Y Gene Polymorphisms Confer Risk of Early-Onset Atherosclerosis

Abstract

Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58–2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46–1.65, p = 0.01–0.05), showing stronger association in youngest cases (OR 1.84–2.20, p = 0.0004–0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79–2.06, p = 0.003–0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor–antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.

Polymorphisms in LEP and NPY genes modify the response to soluble fibre Plantago ovata husk intake on cardiovascular risk biomarkers

“…In accordance with this, numerous studies have observed that the rs16147 G allele increases NPY expression (Itokawa et al 2003;Shah et al 2009). Our results support a role for the NPY gene in modulating hypertension and implicate the rs16147 polymorphism in a magnified response to soluble fibre consumption on sBP, particularly in those homozygous for allele A.…”

Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies

“…Human studies were conducted to determine genetic effects on the relationship between aging and atherosclerosis in two independent cohorts comprising subjects spanning the age range of 18-91 years (12). Our mouse atherosclerosis studies were conducted by transplanting into young Apoe 2/2 mice carotid arteries from aged or young mice that were either wild-type (WT) or Tnfr1 2/2 (4).…”

Neuropeptide Y and Stress

“…[66][67][68][69][70] Shah ve arkadaşları, damarsal peptid hormonunu bloke ederek beyinde NPY'nin bağımsız rolünü ve ateroskleroz tedavisinde yararlı olabileceğini bulmuşlardır. [71] İnsanlarda erken dönem koroner arter hastalıkları ile NPY üretimini sağlayan genin mutasyonları arasında bir ilişki olduğu saptanmıştır.…”