Shah Svati H, Freedman Neil J, Zhang Lisheng, Crosslin David R, Stone David H, Haynes Carol, Johnson Jessica, Nelson Sarah, Wang Liyong, Connelly Jessica J, Muehlbauer Michael, Ginsburg Geoffrey S, Crossman David C, Jones Christopher J H, Vance Jeffery, Sketch Michael H, Granger Christopher B, Newgard Christopher B, Gregory Simon G, Goldschmidt-Clermont Pascal J, Kraus William E, Hauser Elizabeth R
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
PLoS Genet. 2009 Jan;5(1):e1000318. doi: 10.1371/journal.pgen.1000318. Epub 2009 Jan 2.
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.
神经肽Y（NPY）是冠状动脉疾病（CAD）的一个强有力的候选基因。我们之前已在NPY的基因组区域发现与家族性CAD的基因连锁。我们对早发性CAD中的NPY进行了后续的基因、生物统计学及功能分析。在家族性CAD（GENECARD研究，N = 420个家系）中，我们在97个发病年龄最早的家系中发现与7号染色体p14区域的微卫星连锁增加（OSA LOD = 4.2，p = 0.004）。标记的NPY单核苷酸多态性（SNP）显示一个6-SNP区域与CAD存在连锁（LOD = 1.58 - 2.72），该区域与CAD存在基于家系的关联（p = 0.02），且在发病年龄最早的家系中与CAD的连锁更强。这个6-SNP区域与CAD的关联在以下情况得到验证：（a）556例非家族性早发性CAD病例和256例对照（比值比1.46 - 1.65，p = 0.01 - 0.05），在最年轻的病例中关联更强（比值比1.84 - 2.20，p = 0.0004 - 0.09）；以及（b）GENECARD研究中的先证者与非家族性对照（比值比1.79 - 2.06，p = 0.003 - 0.02）。这个6-SNP区域内的一个启动子SNP（rs16147）与更高的血浆NPY水平相关（p = 0.04）。为评估NPY在动脉粥样硬化中的因果作用，我们将NPY1受体拮抗剂BIBP - 3226外用于载脂蛋白E缺陷小鼠的内皮剥脱颈动脉；治疗使动脉粥样硬化新生内膜面积减少50%（p = 0.03）。因此，NPY变异在两个独立数据集中与动脉粥样硬化相关（有显著的发病年龄效应），并显示出与NPY水平的等位基因特异性表达，而NPY受体拮抗作用可减轻小鼠的动脉粥样硬化。我们得出结论，NPY促成动脉粥样硬化的发病机制。
