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

Shah SH, Freedman NJ, Zhang L, Crosslin DR, Stone DH, Haynes C, Johnson J, Nelson S, Wang L, Connelly JJ, Muehlbauer M, Ginsburg GS, Crossman DC, Jones CJ, Vance J, Sketch MH, Granger CB, Newgard CB, Gregory SG, Goldschmidt-Clermont PJ, Kraus WE, Hauser ER - PLoS Genet. (2009)

Bottom Line: 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.A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04).We conclude that NPY contributes to atherosclerosis pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.

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.

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Rs16147 is associated with higher plasma NPY levels.NPY levels were measured in fasting plasma (N = 220). Box-and-whisker plots are presented displaying mean (+), median, and 25–75th interquartile range (shaded boxes), according to number of risk alleles at rs16147. *P = 0.04 for comparison of 1 or 2 vs. 0 risk alleles.
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pgen-1000318-g003: Rs16147 is associated with higher plasma NPY levels.NPY levels were measured in fasting plasma (N = 220). Box-and-whisker plots are presented displaying mean (+), median, and 25–75th interquartile range (shaded boxes), according to number of risk alleles at rs16147. *P = 0.04 for comparison of 1 or 2 vs. 0 risk alleles.

Mentions: To examine allele-specific effects, we assessed the relationship of NPY variants with peripheral NPY levels in 220 subjects randomly selected from the CATHGEN case/control dataset. We found that rs16147 was associated with higher NPY levels for the minor (risk, G) allele compared with the major (A) allele (46.3 vs. 41.0 pmol/L, p = 0.04, Figure 3). Concordantly, NPY levels were higher in CAD cases compared with controls (46.8 vs. 41.1 pmol/L, p = 0.02).


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

Shah SH, Freedman NJ, Zhang L, Crosslin DR, Stone DH, Haynes C, Johnson J, Nelson S, Wang L, Connelly JJ, Muehlbauer M, Ginsburg GS, Crossman DC, Jones CJ, Vance J, Sketch MH, Granger CB, Newgard CB, Gregory SG, Goldschmidt-Clermont PJ, Kraus WE, Hauser ER - PLoS Genet. (2009)

Rs16147 is associated with higher plasma NPY levels.NPY levels were measured in fasting plasma (N = 220). Box-and-whisker plots are presented displaying mean (+), median, and 25–75th interquartile range (shaded boxes), according to number of risk alleles at rs16147. *P = 0.04 for comparison of 1 or 2 vs. 0 risk alleles.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2602734&req=5

pgen-1000318-g003: Rs16147 is associated with higher plasma NPY levels.NPY levels were measured in fasting plasma (N = 220). Box-and-whisker plots are presented displaying mean (+), median, and 25–75th interquartile range (shaded boxes), according to number of risk alleles at rs16147. *P = 0.04 for comparison of 1 or 2 vs. 0 risk alleles.
Mentions: To examine allele-specific effects, we assessed the relationship of NPY variants with peripheral NPY levels in 220 subjects randomly selected from the CATHGEN case/control dataset. We found that rs16147 was associated with higher NPY levels for the minor (risk, G) allele compared with the major (A) allele (46.3 vs. 41.0 pmol/L, p = 0.04, Figure 3). Concordantly, NPY levels were higher in CAD cases compared with controls (46.8 vs. 41.1 pmol/L, p = 0.02).

Bottom Line: 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.A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04).We conclude that NPY contributes to atherosclerosis pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.

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.

Show MeSH
Related in: MedlinePlus