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-ClermontWilliam E. Kraus, Elizabeth R. Hauser

Research output: Contribution to journalArticle

77 Scopus citations

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.

Original languageEnglish (US)
Article numbere1000318
JournalPLoS genetics
Volume5
Issue number1
DOIs
StatePublished - Jan 2009

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Shah, S. H., Freedman, N. J., Zhang, L., Crosslin, D. R., Stone, D. H., Haynes, C., Johnson, J., Nelson, S., Wang, L., Connelly, J. J., Muehlbauer, M., Ginsburg, G. S., Crossman, D. C., Jones, C. J. H., Vance, J., Sketch, M. H., Granger, C. B., Newgard, C. B., Gregory, S. G., ... Hauser, E. R. (2009). Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis. PLoS genetics, 5(1), [e1000318]. https://doi.org/10.1371/journal.pgen.1000318