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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.

SUBMITTER: Shah SH

PROVIDER: S-EPMC2602734 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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

Shah Svati H SH 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

PLoS genetics 20090102 1

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 ...[more]

PMID: 19119412

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Project description:The circulating concentrations of triglycerides, high density lipoprotein (HDL)?cholesterol, and low density lipoprotein (LDL)?cholesterol have a substantial genetic component, and the heritability of early?onset dyslipidemia might be expected to be higher compared with late?onset forms. In the present study, exome?wide association studies (EWASs) were performed for early?onset hypertriglyceridemia, hypo?HDL?cholesterolemia, and hyper?LDL?cholesterolemia, with the aim to identify genetic variants that confer susceptibility to these conditions in the Japanese population. A total of 8,073 individuals aged ?65 years were enrolled in the study. The EWASs for hypertriglyceridemia (2,664 cases and 5,294 controls), hypo?HDL?cholesterolemia (974 cases and 7,085 controls), and hyper?LDL?cholesterolemia (2,911 cases and 5,111 controls) were performed with Illumina Human Exome?12 v1.2 DNA Analysis BeadChip or Infinium Exome?24 v1.0 BeadChip arrays. The association of allele frequencies for 31,198, 31,133, or 31,175 single nucleotide polymorphisms (SNPs) to hypertriglyceridemia, hypo?HDL?cholesterolemia, or hyper?LDL?cholesterolemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with each of the three conditions, Bonferroni's correction was applied for statistical significance of association. The results demonstrated that 25, 28 and 65 SNPs were significantly associated with hypertriglyceridemia, hypo?HDL?cholesterolemia and hyper?LDL?cholesterolemia, respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that all 25, 28 and 65 of these SNPs were significantly associated with hypertriglyceridemia, hypo?HDL?cholesterolemia and hyper?LDL?cholesterolemia, respectively. Following examination of the association of the identified SNPs to serum concentrations of triglycerides, HDL?cholesterol, or LDL?cholesterol, linkage disequilibrium of the SNPs, and results of previous genome?wide association studies, we newly identified chromosomal region 19p12 as a susceptibility locus for hypertriglyceridemia, eight loci (MOB3C?TMOD4, LPGAT1, EHD3, COL6A3, ZNF860?CACNA1D, COL6A5, DCLRE1C, ZNF77) for hypo?HDL?cholesterolemia, and three loci (KIAA0319?FAM65B, UBD, LOC105375015) for hyper?LDL?cholesterolemia. The present study thus identified 12 novel loci that may confer susceptibility to early?onset dyslipidemia. Determination of genotypes for the SNPs at these loci may prove informative for assessment of genetic risk for hypertriglyceridemia, hypo?HDL?cholesterolemia, or hyper?LDL?cholesterolemia in the Japanese population.

Dataset Information

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

Publications

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

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