Id3 is a novel atheroprotective factor containing a functionally significant single-nucleotide polymorphism associated with intima-media thickness in humans.
Id3 is a novel atheroprotective factor containing a functionally significant single-nucleotide polymorphism associated with intima-media thickness in humans.
复制标题
DOI：
10.1161/circresaha.109.210294
复制
发表时间：
2010-04-16
影响因子：
20.1
通讯作者：
McNamara CA
中科院分区：
文献类型：
--
作者：
Doran AC;Lehtinen AB;Meller N;Lipinski MJ;Slayton RP;Oldham SN;Skaflen MD;Yeboah J;Rich SS;Bowden DW;McNamara CA
编码螺旋-环-螺旋转录因子Id 3的基因位于小鼠和人的动脉粥样硬化易感基因座内，但其对动脉粥样硬化的影响尚不清楚。本研究旨在确定ID 3基因多态性是否与人类动脉粥样硬化指数相关，以及Id 3功能丧失是否调节小鼠动脉粥样硬化形成。在糖尿病心脏研究的参与者中评估了人类ID 3基因中的六个标签SNP（tagSNP）。其中一个tagSNP rs 11574与颈动脉内膜中层厚度（IMT）独立相关。在rs 11574处的人ID 3变体导致C-末端中丙氨酸至苏氨酸的取代。为了确定这种多态性对Id 3的基本功能的影响，进行了人ID 3基因在rs 11574处的定点诱变。结果表明，当已知的E蛋白伴侣E12含有由风险等位基因（Id 3105 T）编码的序列时，其与Id 3的免疫共沉淀显著减少。此外，与含有祖先等位基因的Id 3（Id 3105 A）相比，Id 3105 T具有减弱的调节E12介导的转录激活的能力。WT和Id 3-/-小鼠血管平滑肌细胞的微阵列分析揭示了动脉粥样硬化形成中涉及的多个基因通路的显著调节。此外，与Id 3 +/+ ApoE-/-小鼠相比，Id 3-/- ApoE-/-小鼠在32周的普通饲料或西方饮食喂养中发生了显著更多的动脉粥样硬化。总之，结果提供了新的证据，即Id 3是一种动脉粥样硬化保护因子，并将人类ID 3基因中的一个常见SNP与Id 3功能丧失和IMT增加联系起来。
The gene encoding the helix-loop-helix transcription factor, Id3, is located within atherosclerosis susceptibility loci of both mice and humans, yet its influence on atherosclerosis is not known. The present study sought to determine if polymorphisms in the ID3 gene were associated with indices of atherosclerosis in humans and if loss of Id3 function modulated atherogenesis in mice. Six tagging SNPs (tagSNPs) in the human ID3 gene were assessed in participants of the Diabetes Heart Study. One tagSNP, rs11574, was independently associated with carotid intima-media thickness (IMT). The human ID3 variant at rs11574 results in an alanine to threonine substitution in the C-terminus. To determine the effect of this polymorphism on the basic function of Id3, site-directed mutagenesis of the human ID3 gene at rs11574 was performed. Results demonstrated a significant reduction in co-immunoprecipitation of the known E-protein partner, E12, with Id3 when it contains the sequence encoded by the risk allele (Id3105T). Further, Id3105T had an attenuated ability to modulate E12-mediated transcriptional activation compared to Id3 containing the ancestral allele (Id3105A). Microarray analysis of vascular smooth muscle cells from WT and Id3-/- mice revealed significant modulation of multiple gene pathways implicated in atherogenesis. Moreover, Id3-/- ApoE-/- mice developed significantly more atherosclerosis in response to 32 weeks of Chow or Western diet feeding than Id3+/+ApoE-/- mice. Taken together, results provide novel evidence that Id3 is an atheroprotective factor and link a common SNP in the human ID3 gene to loss of Id3 function and increased IMT.