PLoS Genetics (Jan 2009)

Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.

  • 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

DOI
https://doi.org/10.1371/journal.pgen.1000318
Journal volume & issue
Vol. 5, no. 1
p. e1000318

Abstract

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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.