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

dc.contributor.author Connelly, Jessica J
dc.contributor.author Crosslin, DR
dc.contributor.author Crossman, DC
dc.contributor.author Freedman, NJ
dc.contributor.author Ginsburg, Geoffrey Steven
dc.contributor.author Goldschmidt-Clermont, PJ
dc.contributor.author Granger, CB
dc.contributor.author Gregory, Simon Gray
dc.contributor.author Hauser, Elizabeth Rebecca
dc.contributor.author Haynes, Carol
dc.contributor.author Johnson, J
dc.contributor.author Jones, CJH
dc.contributor.author Kraus, William Erle
dc.contributor.author Muehlbauer, Michael J
dc.contributor.author Nelson, S
dc.contributor.author Newgard, Christopher Bang
dc.contributor.author Shah, SH
dc.contributor.author Sketch, MH
dc.contributor.author Stone, DH
dc.contributor.author Vance, J
dc.contributor.author Wang, L
dc.contributor.author Zhang, L
dc.coverage.spatial United States
dc.date.accessioned 2018-02-01T19:38:51Z
dc.date.available 2018-02-01T19:38:51Z
dc.date.issued 2009-01
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/19119412
dc.identifier.uri https://hdl.handle.net/10161/16064
dc.description.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.
dc.language eng
dc.relation.ispartof PLoS Genet
dc.relation.isversionof 10.1371/journal.pgen.1000318
dc.subject Age of Onset
dc.subject Alleles
dc.subject Animals
dc.subject Arginine
dc.subject Atherosclerosis
dc.subject Female
dc.subject Genetic Predisposition to Disease
dc.subject Genotype
dc.subject Humans
dc.subject Linkage Disequilibrium
dc.subject Lod Score
dc.subject Male
dc.subject Mice
dc.subject Mice, Transgenic
dc.subject Middle Aged
dc.subject Neuropeptide Y
dc.subject Polymorphism, Genetic
dc.subject Receptors, Neuropeptide Y
dc.title Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/19119412
pubs.begin-page e1000318
pubs.issue 1
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biochemistry
pubs.organisational-group Biostatistics & Bioinformatics
pubs.organisational-group Cell Biology
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Clinical Research Institute
pubs.organisational-group Duke Global Health Institute
pubs.organisational-group Duke Molecular Physiology Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Cardiology
pubs.organisational-group Medicine, Endocrinology, Metabolism, and Nutrition
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Neurology
pubs.organisational-group Neurology, MS & Neuroimmunology
pubs.organisational-group Nursing
pubs.organisational-group Pathology
pubs.organisational-group Pharmacology & Cancer Biology
pubs.organisational-group School of Medicine
pubs.organisational-group School of Nursing
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published
pubs.volume 5
dc.identifier.eissn 1553-7404


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