Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.
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.
Shah
Svati H
SH
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
Freedman
Neil J
NJ
Zhang
Lisheng
L
Crosslin
David R
DR
Stone
David H
DH
Haynes
Carol
C
Johnson
Jessica
J
Nelson
Sarah
S
Wang
Liyong
L
Connelly
Jessica J
JJ
Muehlbauer
Michael
M
Ginsburg
Geoffrey S
GS
Crossman
David C
DC
Jones
Christopher J H
CJ
Vance
Jeffery
J
Sketch
Michael H
MH
Granger
Christopher B
CB
Newgard
Christopher B
CB
Gregory
Simon G
SG
Goldschmidt-Clermont
Pascal J
PJ
Kraus
William E
WE
Hauser
Elizabeth R
ER
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
C092926:BIBP 3226; D009478:Neuropeptide Y; C507698:Npy1r protein, mouse; D017476:Receptors, Neuropeptide Y; D001120:Arginine