Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Curr Opin Cardiol. 2012 May;27(3):210-3. doi: 10.1097/HCO.0b013e3283522198.
Genome-wide association studies have led to the discovery of many single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). However, many of these SNPs are in between genes (intergenic), and presumably function through the regulation of gene expression. Microarrays that measure the expression of thousands of mRNAs have allowed investigators to study how genetic variation alters gene expression at a genome-wide level. Combining these methods has led to progress in understanding the molecular basis for the genetic susceptibility to atherosclerosis.
Recent studies confirm that gene expression differences due to genetic variation play an underlying role in atherosclerosis. Expression levels of SORT1 are negatively correlated with an intergenic risk allele on chromosome 1p13.3 that was previously associated with CAD. Increased SORT1 expression leads to lower hepatic secretion of low-density lipoprotein (LDL), providing a mechanistic link between a common risk variant and disease. In addition, three out of 13 newly identified CAD risk loci were found to strongly affect the expression of nearby genes. Another recent study detected variants adjacent to a newly identified atherosclerosis risk locus on chromosome 11q22 that were associated with the expression of platelet-derived growth factor D (PDGFD).
Cataloging the genetics of gene expression provides a small but crucial molecular link between genetics and clinical phenotypes such as atherosclerosis. Thus, gene expression is an endophenotype that can lead to the discovery of the underlying genes responsible for increasing atherosclerosis risk and potential diagnostic and therapeutic targets.
全基因组关联研究发现了许多与冠心病（CAD）相关的单核苷酸多态性（SNPs）。然而，许多这些 SNPs 位于基因之间（基因间），推测通过基因表达的调控起作用。测量数千个 mRNA 表达的微阵列使研究人员能够研究遗传变异如何在全基因组水平上改变基因表达。这些方法的结合有助于理解动脉粥样硬化遗传易感性的分子基础。
最近的研究证实，遗传变异引起的基因表达差异在动脉粥样硬化中起着潜在的作用。SORT1 的表达水平与先前与 CAD 相关的 1p13.3 染色体上的基因间风险等位基因呈负相关。SORT1 表达的增加导致低密度脂蛋白（LDL）在肝脏中的分泌降低，为常见风险变异体与疾病之间提供了一个机制联系。此外，在 13 个新确定的 CAD 风险位点中，有 3 个被发现强烈影响附近基因的表达。另一项最近的研究检测到 11q22 染色体上新发现的动脉粥样硬化风险位点附近的变体与血小板衍生生长因子 D（PDGFD）的表达有关。
基因表达遗传学的编目为遗传学和临床表型（如动脉粥样硬化）之间提供了一个小但至关重要的分子联系。因此，基因表达是一个内表型，可以导致发现增加动脉粥样硬化风险的潜在基因以及潜在的诊断和治疗靶点。
