title: 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.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Freedman
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.forename: David H
authors.initials: DH
authors.lastname: Stone
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.forename: Sarah
authors.initials: S
authors.lastname: Nelson
authors.forename: Liyong
authors.initials: L
authors.lastname: Wang
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Connelly
authors.forename: Michael
authors.initials: M
authors.lastname: Muehlbauer
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Ginsburg
authors.forename: David C
authors.initials: DC
authors.lastname: Crossman
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Jones
authors.forename: Jeffery
authors.initials: J
authors.lastname: Vance
authors.forename: Michael H
authors.initials: MH
authors.lastname: Sketch
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009478:Neuropeptide Y / Q000235:genetics*; D011110:Polymorphism, Genetic; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C092926:BIBP 3226; D009478:Neuropeptide Y; C507698:Npy1r protein, mouse; D017476:Receptors, Neuropeptide Y; D001120:Arginine