Genetic and functional association of FAM5C with myocardial infarction.
Genetic and functional association of FAM5C with myocardial infarction.
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FAM5C与心肌梗塞的遗传和功能关联。
DOI：
10.1186/1471-2350-9-33
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发表时间：
2008-04-22
影响因子：
--
通讯作者：
Gregory, Simon G.
中科院分区：
文献类型：
--
作者：
Connelly, Jessica J.;Shah, Svati H.;Doss, Jennifer F.;Gadson, Shera;Nelson, Sarah;Crosslin, David R.;Hale, A. Brent;Lou, Xuemei;Wang, Ty;Haynes, Carol;Seo, David;Crossman, David C.;Mooser, Vincent;Granger, Christopher B.;Jones, Christopher J. H.;Kraus, William E.;Hauser, Elizabeth R.;Gregory, Simon G.
我们先前在早发性冠状动脉疾病（CAD）全基因组连锁扫描（GENECARD）中发现了染色体1 q上的40 Mb连锁区域，并有适度的连锁证据（n = 420，LOD 0.95）。当按急性冠脉综合征（ACS）对数据进行分层时，整个组中的这一适度最大值变成了明确定义的LOD峰值（最大LOD为2.17，D1 S1589/D1 S518）。该峰与最近在Frachial Heart研究中确定的炎症生物标志物（MCP-1）连锁区域（最大LOD为4.27，D1 S1589）和IRAS研究中与代谢综合征连锁的区域（最大LOD为2.59，D1 S1589/D1 S518）重叠。在独立的数据集遗传屏幕的重叠提供了证据，在该地区的CAD基因的存在。在一个以家族为基础的早发性冠状动脉疾病（CAD）样本（GENECARD）中，对1号染色体上急性冠状动脉综合征（ACS）连锁峰中从峰值标记（168-198 Mb）向下的区域1 LOD评分进行了全峰关联筛选（457个SNP）。在GENECARD中，在“具有序列相似性5的家族成员C”基因（FAM 5C）中鉴定了与心肌梗死（MI）相关的遗传连锁的多态性。在一个独立的CAD病例对照样本（CATHGEN）中证实了这种关联，并通过FAM 5C 3'端的单核苷酸多态性（SNP）鉴定了与MI的强关联。FAM 5C基因型也与主动脉中该基因的表达相关。FAM 5C的表达水平随着增殖的主动脉平滑肌细胞（SMC）传代次数的增加而降低，表明该分子在平滑肌细胞增殖和衰老中的作用。这些数据暗示FAM 5C等位基因在心肌梗死的风险，并建议进一步的功能研究FAM 5C需要确定该基因的动脉粥样硬化的贡献。
We previously identified a 40 Mb region of linkage on chromosome 1q in our early onset coronary artery disease (CAD) genome-wide linkage scan (GENECARD) with modest evidence for linkage (n = 420, LOD 0.95). When the data are stratified by acute coronary syndrome (ACS), this modest maximum in the overall group became a well-defined LOD peak (maximum LOD of 2.17, D1S1589/D1S518). This peak overlaps a recently identified inflammatory biomarker (MCP-1) linkage region from the Framingham Heart Study (maximum LOD of 4.27, D1S1589) and a region of linkage to metabolic syndrome from the IRAS study (maximum LOD of 2.59, D1S1589/D1S518). The overlap of genetic screens in independent data sets provides evidence for the existence of a gene or genes for CAD in this region. A peak-wide association screen (457 SNPs) was conducted of a region 1 LOD score down from the peak marker (168–198 Mb) in a linkage peak for acute coronary syndrome (ACS) on chromosome 1, within a family-based early onset coronary artery disease (CAD) sample (GENECARD). Polymorphisms were identified within the 'family with sequence similarity 5, member C' gene (FAM5C) that show genetic linkage to and are associated with myocardial infarction (MI) in GENECARD. The association was confirmed in an independent CAD case-control sample (CATHGEN) and strong association with MI was identified with single nucleotide polymorphisms (SNPs) in the 3' end of FAM5C. FAM5C genotypes were also correlated with expression of the gene in human aorta. Expression levels of FAM5C decreased with increasing passage of proliferating aortic smooth muscle cells (SMC) suggesting a role for this molecule in smooth muscle cell proliferation and senescence. These data implicate FAM5C alleles in the risk of myocardial infarction and suggest further functional studies of FAM5C are required to identify the gene's contribution to atherosclerosis.
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