Winther-Larsen Anne, Christiansen Morten Krogh, Larsen Sanne Bøjet, Nyegaard Mette, Neergaard-Petersen Søs, Ajjan Ramzi A, Würtz Morten, Grove Erik Lerkevang, Jensen Henrik Kjærulf, Kristensen Steen Dalby, Hvas Anne-Mette
Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Biochemistry, Viborg Regional Hospital, Viborg, Denmark.
Thromb Haemost. 2020 Sep;120(9):1248-1256. doi: 10.1055/s-0040-1713753. Epub 2020 Jun 30.
The locus has been associated with increased risk of myocardial infarction (MI) in patients with coronary artery disease (CAD), but the underlying mechanisms are unknown. As altered fibrin clot structure has been demonstrated to predict MI in CAD patients, we examined the association between the risk variant and fibrin clot properties, and investigated the effects of other CAD-associated risk variants.
We included 773 stable CAD patients. Patients were genotyped for 45 genome-wide CAD risk variants, including rs495828 at the locus. We used a genetic risk score (GRS) for CAD calculated as the weighted sum of the number of risk alleles based on all 45 variants. Fibrin clot properties were evaluated using a turbidimetric assay. We studied clot maximum absorbance, a measure of clot density and fiber thickness, together with clot lysis time, an indicator of fibrinolysis potential.
The rs495828 risk allele was present in 13.2% of patients and associated with higher clot maximum absorbance (adjusted effect size per risk allele: 1.05 [1.01 - 1.09], = 0.01) but not with clot lysis time ( = 0.97). The rs12936587 ( = 0.04), rs4773144 ( = 0.02), and rs501120 ( = 0.04) were associated with clot lysis time; however, after Bonferroni correction, no significant associations were found between any of the remaining 44 CAD-associated variants and fibrin clot properties. The GRS was not associated with fibrin clot properties (-values > 0.05).
The risk allele was associated with a more compact fibrin network in stable CAD patients, which may represent a mechanism for increased MI risk in risk variant carriers.
该基因座与冠状动脉疾病（CAD）患者心肌梗死（MI）风险增加相关，但其潜在机制尚不清楚。由于已证明纤维蛋白凝块结构改变可预测CAD患者的MI，我们研究了该风险变异与纤维蛋白凝块特性之间的关联，并调查了其他CAD相关风险变异的影响。
我们纳入了773例稳定型CAD患者。对患者进行了45个全基因组CAD风险变异的基因分型，包括该基因座的rs495828。我们使用基于所有45个变异的风险等位基因数量的加权和计算的CAD遗传风险评分（GRS）。使用比浊法评估纤维蛋白凝块特性。我们研究了凝块最大吸光度（一种凝块密度和纤维厚度的测量指标）以及凝块溶解时间（纤维蛋白溶解潜力的指标）。
13.2%的患者存在rs495828风险等位基因，其与更高的凝块最大吸光度相关（每个风险等位基因的调整效应大小：1.05 [1.01 - 1.09]，P = 0.01），但与凝块溶解时间无关（P = 0.97）。rs12936587（P = 0.04）、rs4773144（P = 0.02）和rs501120（P = 0.04）与凝块溶解时间相关；然而，经过Bonferroni校正后，其余44个CAD相关变异与纤维蛋白凝块特性之间均未发现显著关联。GRS与纤维蛋白凝块特性无关（P值> 0.05）。
该风险等位基因与稳定型CAD患者中更致密的纤维蛋白网络相关，这可能是该风险变异携带者MI风险增加的一种机制。
