Vanderbilt Genetics Institute, Vanderbilt University Medical School, Nashville, TN, USA; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA; Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical School, Nashville, TN, USA; Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
Glob Heart. 2017 Jun;12(2):133-140. doi: 10.1016/j.gheart.2017.01.013. Epub 2017 Apr 10.
Plasma concentration of plasminogen activator inhibitor-1 (PAI-1) is highly correlated with several cardiovascular disease (CVD) risk factors. It also plays a direct role in CVD, including myocardial infarction and stroke, by impeding the dissolution of thrombi in the blood. Insofar as PAI-1 links CVD's risk factors to its endpoints, genetic variants modulating the relationship between PAI-1 and risk factors may be of particular clinical and biological interest. The high heritability of PAI-1, which has not been explained by genetic association studies, may also, in large part, be due to this relationship with CVD risk factors. Using exome-wide data from 1,032 Ghanaian study participants, we tested for heterogeneity of correlation by genotype between PAI-1 and 4 CVD risk factors (body mass index, triglycerides, mean arterial pressure, and fasting glucose) under the hypothesis that loci involved in the relationship between PAI-1 and other risk factors will also modify their correlational structure. We found more significant heterogeneities of correlation by genotype than we found marginal effects, with no evidence of type I inflation. The most significant result among all univariate and multivariate tests performed in this study was the heterogeneity of correlation between PAI-1 and mean arterial pressure at rs10738554, near SLC24A2, a gene previously associated with high blood pressure in African Americans.
血浆纤溶酶原激活物抑制剂-1（PAI-1）的浓度与多种心血管疾病（CVD）风险因素高度相关。它还通过阻碍血液中血栓的溶解，直接参与 CVD，包括心肌梗死和中风。由于 PAI-1 将 CVD 的风险因素与其终点联系起来，因此调节 PAI-1 与风险因素之间关系的遗传变异可能具有特别的临床和生物学意义。PAI-1 的高遗传性尚未通过遗传关联研究得到解释，这在很大程度上也可能是由于它与 CVD 风险因素的关系。利用来自 1032 名加纳研究参与者的外显子组数据，我们根据假设，即参与 PAI-1 与其他风险因素之间关系的基因座也会改变它们的相关结构，测试了 PAI-1 与 4 个 CVD 风险因素（体重指数、甘油三酯、平均动脉压和空腹血糖）之间基因型相关性的异质性。我们发现，与边缘效应相比，基因型相关性的异质性更多，且不存在 I 型膨胀。在本研究进行的所有单变量和多变量检验中，最显著的结果是 rs10738554 附近 SLC24A2 基因处 PAI-1 与平均动脉压之间相关性的异质性，该基因先前与非裔美国人的高血压有关。
