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.

• Authors: Svati H Shah, Neil J Freedman, Lisheng Zhang, David R Crosslin, David H Stone, Carol Haynes, Jessica Johnson, Sarah Nelson, Liyong Wang, Jessica J Connelly, Michael Muehlbauer, Geoffrey S Ginsburg, David C Crossman, Christopher J H Jones, Jeffery Vance, Michael H Sketch, Christopher B Granger, Christopher B Newgard, Simon G Gregory, Pascal J Goldschmidt-Clermont, William E Kraus, Elizabeth R Hauser
• Journal: PLoS genetics (PLoS Genet) Vol. 5 Issue 1 Pg. e1000318 (Jan 2009) ISSN: 1553-7404 [Electronic] United States
• PMID: 19119412 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BIBP 3226
• Neuropeptide Y
• Npy1r protein, mouse
• Receptors, Neuropeptide Y
• Arginine

Topics

• Age of Onset
• Alleles
• Animals
• Arginine (analogs & derivatives, pharmacology)
• Atherosclerosis (epidemiology, genetics)
• Female
• Genetic Predisposition to Disease (genetics)
• Genotype
• Humans
• Linkage Disequilibrium
• Lod Score
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Neuropeptide Y (genetics)
• Polymorphism, Genetic
• Receptors, Neuropeptide Y (antagonists & inhibitors, genetics, metabolism)