Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis.
Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis.
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DOI：
10.1007/s00439-008-0619-0
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发表时间：
2009-03
期刊：
影响因子：
5.3
通讯作者：
Hauser ER
中科院分区：
文献类型：
--
作者：
Crosslin DR;Shah SH;Nelson SC;Haynes CS;Connelly JJ;Gadson S;Goldschmidt-Clermont PJ;Vance JM;Rose J;Granger CB;Seo D;Gregory SG;Kraus WE;Hauser ER
白三烯是花生四烯酸的衍生物，长期以来因其炎症特性而闻名，并与许多人类疾病有关，尤其是哮喘。最近，基于白三烯的炎症也被证明在动脉粥样硬化中起重要作用：白三烯生物合成途径中的两个基因ALOX5AP和LTA4H分别被证明与各种心血管疾病(CVD)表型相关。为了评估白三烯途径在心血管疾病发病机制中的作用，我们在早发性冠状动脉疾病(EOCAD)家族研究(GENECARD，1,101个家系)和EOCAD非家族数据集(CATHGEN，656例患者和405名对照)中进行了ALOX5AP和LTA4H的基因关联研究。我们发现ALOX5AP和LTA4H的单核苷酸多态(SNPs)与EOCAD之间存在弱到中度的关联。在控制了年龄、种族和心血管危险因素后，先前报道的ALOX5AP的4-SNP单倍型(HAPA)与CATHGEN的EOCAD相关(P=0.02)。已报道的LTA4H单倍型HapK与CATHGEN的EOCAD相关(P=0.04)。另一个先前报道的ALOX5AP(HapB)的4-SNP单倍型在我们的样本中没有显著意义(P=0.39)。与单倍型结果相比，总体上缺乏(或弱)单个SNPs的相关性，这表明在此类研究中需要分析每个基因内的多个SNPs。有趣的是，我们检测到ALOX5(P<；0.05)--ALOX5AP的靶标--的SNPs与心血管疾病的关联。使用基于途径的方法，我们还利用收集的具有不同程度动脉粥样硬化的新鲜人主动脉的RNA表达数据，检测了ALOX5、ALOX5AP和LTA4H之间相互作用的统计证据。GENECARD家族没有证据表明与ALOX5、ALOX5AP或LTA4H存在连锁或关联。我们的结果支持白三烯途径在动脉粥样硬化发病机制中的适度作用，揭示了该途径中重要的基因组相互作用，并表明使用基于途径的模型来评估动脉粥样硬化易感性的基因组学的重要性。
Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of human diseases, most particularly asthma. Recently, leukotriene-based inflammation has also been shown to play an important role in atherosclerosis: ALOX5AP and LTA4H, both genes in the leukotriene biosynthesis pathway, have individually been shown to be associated with various cardiovascular disease (CVD) phenotypes. To assess the role of the leukotriene pathway in CVD pathogenesis, we performed genetic association studies of ALOX5AP and LTA4H in a family based study of early onset coronary artery disease (EOCAD) (GENECARD, 1,101 families) and in a non-familial dataset of EOCAD (CATHGEN, 656 cases and 405 controls). We found weak to moderate association between single nucleotide polymorphisms (SNPs) in ALOX5AP and LTA4H with EOCAD. The previously reported four-SNP haplotype (HapA) in ALOX5AP showed association with EOCAD in CATHGEN (P = 0.02), while controlling for age, race and CVD risk factors. HapK, the previously reported ten-SNP haplotype in LTA4H was associated with EOCAD in CATHGEN (P = 0.04). Another previously reported four-SNP haplotype in ALOX5AP (HapB) was not significant in our sample (P = 0.39). The overall lack of (or weak) association of single SNPs as compared with the haplotype results demonstrates the need for analyzing multiple SNPs within each gene in such studies. Interestingly, we detected an association of SNPs in ALOX5 (P < 0.05), the target of ALOX5AP, with CVD. Using a pathway-based approach, we also detected statistical evidence for interactions among ALOX5, ALOX5AP and LTA4H using RNA expression data from a collection of freshly harvested human aortas with varying degrees of atherosclerosis. The GENECARD families did not demonstrate evidence for linkage or association with ALOX5, ALOX5AP or LTA4H. Our results support a modest role for the leukotriene pathway in atherosclerosis pathogenesis, reveal important genomic interactions within the pathway, and suggest the importance of using pathway-based modeling for evaluating the genomics of atherosclerosis susceptibility.
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DOI：
10.1161/01.atv.0000141358.65242.1f
发表时间：
2004-10-01
影响因子：
8.7
作者：
Seo, D;Wang, T;Goldschmidt-Clermont, PJ
通讯作者：
Goldschmidt-Clermont, PJ
影响因子：
8.3
作者：
Lohmussaar, E;Gschwendtner, A;Dichgans, M
通讯作者：
Dichgans, M
影响因子：
2.1
作者：
Blangero, J;Williams, JT;Almasy, L
通讯作者：
Almasy, L
DOI：
10.1161/01.atv.0000172632.96987.2d
发表时间：
2005-08-01
影响因子：
8.7
作者：
Cipollone, F;Mezzetti, A;Stafforini, DM
通讯作者：
Stafforini, DM
影响因子：
30.8
作者：
Helgadottir, A;Manolescu, A;Stefansson, K
通讯作者：
Stefansson, K