Genetic determinants of coronary artery calcification progression in the Heinz Nixdorf Recall Study: A Genome-wide association study

动脉粥样硬化是冠状动脉疾病(CAD)的主要原因，在大多数临床明显的冠心病(CHD)病例中，动脉粥样硬化的发病早了几十年。冠状动脉钙化(CAC)是冠状动脉粥样硬化最敏感、最特异的指标之一。据报道，CAC进展的遗传力很强，约占观察到的变异的40%，其中14%的变异可由遗传因素解释。然而，与CAC进展相关的遗传因素几乎是未知的。全基因组关联研究(GWAS)成功地识别和复制了与各种疾病相关的遗传位点，突显了它的重要性。在这项研究中，我们建议在3481名Heinz Nixdorf Recall参与者中进行Gwas方法，以寻找与CAC进展相关的遗传变异。我们将采用两阶段战略(A)发现阶段和(B)验证阶段。在发现阶段，我们将使用最新的基因芯片筛选3481名Heinz Nixdorf Recall参与者，以寻找与CAC进展相关的信号，为期5年。在验证阶段，我们将验证来自Nelson Study的独立样本中的最重要信号(基于P值选择的多达1000个标记)。这项拟议的研究将有助于识别和验证影响CAC进展的基因变异，这可能有助于解释导致CAD的基本机制，并可能有助于制定预防、预测和治疗CAD的策略。

Atherosclerosis is the primary cause of coronary artery disease (CAD) and precedes the onset of most cases of clinically apparent coronary heart disease (CHD) by decades. Coronary artery calcification (CAC) is one of the most sensitive and specific markers of coronary atherosclerotic. The heritability of CAC progression has been reported to be strong, accounting for around 40% of the observed variance with 14% of variation explained by genetic factors. However, the genetic factors that are associated with progression of CAC are almost unknown. The importance of genome-wide association study (GWAS) is highlighted by its success to identify and reproduce genetic loci associated with various diseases. In this study we propose to carry out a GWAS approach in 3,481 Heinz Nixdorf Recall participants to find genetic variants associated with progression of CAC. We will adopt a two-stage strategy (a) discovery phase and (b) validation phase. In the discovery phase we will screen 3,481 Heinz Nixdorf Recall participants using latest genotyping chips to find signals associated with progression of CAC during a 5-year follow-up period. In the validation phase we will validate the top significant signals (up to 1000 markers selected based on P-values) in independent samples from NELSON Study. The proposed study will help to identify and validate genetic variants affecting progression of CAC which may help explain the essential mechanisms leading to CAD and might aid development of strategies to prevent, predict and treat CAD.