The 9p21 susceptibility locus for coronary artery disease and the severity of coronary atherosclerosis.
The 9p21 susceptibility locus for coronary artery disease and the severity of coronary atherosclerosis.
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DOI：
10.1186/1471-2261-9-3
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发表时间：
2009-01-27
影响因子：
2.1
通讯作者：
Marian AJ
中科院分区：
文献类型：
--
作者：
Chen SN;Ballantyne CM;Gotto AM Jr;Marian AJ
病例对照全基因组关联研究（GWAS）已经确定9p21位点的单核苷酸多态性（snp）是冠状动脉疾病（CAD）的危险因素。该位点不包含明确的候选基因。因此，GWAS的结果引起了人们对描述所观察到的关联的基础的强烈兴趣。我们分析了9p21位点上的4个snp与冠状动脉粥样硬化严重程度和进展的相关性，这些snp是通过一系列定量冠状动脉造影（QCA）在特征明确的脂蛋白冠状动脉粥样硬化研究（LCAS）人群中确定的。LCAS是一项针对冠心病患者的随机安慰剂对照纵向随访研究，旨在检验氟伐他汀对冠状动脉粥样硬化进展或消退的影响。在基线和随机分组后2年半测量广泛的血脂水平。同样，在基线和研究完成时也进行了一系列QCA。我们使用荧光5'核酸酶测定法对人群进行了4个snp的基因分型，这些snp先前被确定为GWAS中CAD的易感性snp。我们利用Phase 2重构单倍型，并利用Thesias软件和常规统计方法分析SNP和单倍型效应。只有高加索人被包括在内，因为他们占研究人群的90%（332/371可获得DNA样本）。9p21位点的4个snp处于紧密连锁不平衡状态，导致LCAS群体中存在3种常见的单倍型。我们发现冠状动脉粥样硬化严重程度的定量指标，如最小管腔直径和冠状动脉病变或闭塞的数量与9p21 snp和单倍型之间没有显著的相关性。同样，冠状动脉粥样硬化进展的定量指标与snp或单倍型之间没有关联。同样，我们发现SNP或单倍型对冠状动脉粥样硬化的严重程度和进展没有显著影响。我们得出结论，本研究分析的9p21位点的4个snp对冠状动脉粥样硬化的严重程度或进展没有主要影响。效应大小可能非常有限，或者在病例对照GWAS中观察到的CAD与9p21位点snp的关联反映了与冠状动脉粥样硬化的严重程度或进展没有直接关系的血管机制的参与。
Case-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis. Extensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods. Only Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis. We conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.
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DOI：
10.1056/nejmoa072366
发表时间：
2007-08-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Samani NJ;Erdmann J;Hall AS;Hengstenberg C;Mangino M;Mayer B;Dixon RJ;Meitinger T;Braund P;Wichmann HE;Barrett JH;König IR;Stevens SE;Szymczak S;Tregouet DA;Iles MM;Pahlke F;Pollard H;Lieb W;Cambien F;Fischer M;Ouwehand W;Blankenberg S;Balmforth AJ;Baessler A;Ball SG;Strom TM;Braenne I;Gieger C;Deloukas P;Tobin MD;Ziegler A;Thompson JR;Schunkert H;WTCCC and the Cardiogenics Consortium
通讯作者：
WTCCC and the Cardiogenics Consortium
影响因子：
2.8
作者：
Herd, JA;Ballantyne, CM;Gotto, AM
通讯作者：
Gotto, AM
影响因子：
30.8
作者：
Helgadottir, Anna;Thorleifsson, Gudmar;Stefansson, Kari
通讯作者：
Stefansson, Kari
影响因子：
4
作者：
Farmer, Tiffany E.;Williams, Christopher S.;Washington, M. Kay;Hiebert, Scott W.
通讯作者：
Hiebert, Scott W.
影响因子：
64.5
作者：
Serrano, M;Lee, HW;DePinho, RA
通讯作者：
DePinho, RA