Williams Paul T
Lawrence Berkeley National Laboratory, Molecular Biophysics & Integrated Bioimaging Division, Berkeley, CA, USA.
J Thromb Haemost. 2021 Oct;19(10):2559-2571. doi: 10.1111/jth.15468. Epub 2021 Aug 8.
Plasminogen activator inhibitor type-1 (PAI-1, aka SERPINE1) is a moderately heritable glycoprotein that regulates fibrin clot dissolution (fibrinolysis).
Test whether the heritabilities (h ) of PAI-1 and other hemostatic factors are constant throughout their distribution or whether they are quantile-specific (i.e., a larger or smaller h depending on whether their concentrations are high or low).
Quantile regression was applied to 5606 parent-offspring pairs and 5310 full siblings of the Framingham Heart Study. Quantile-specific heritability was estimated from the parent-offspring regression slope (β , h = 2β /(1+r )) and the full-sib regression slope (β , h = {(1+8r β ) -1}/(2r )).
Heritability (h ± SE) increased significantly with increasing percentiles of the offspring's age- and sex-adjusted PAI-1 distribution when estimated from β (p = 0.0001): 0.09 ± 0.02 at the 10th, 0.09 ± 0.02 at the 25th, 0.16 ± 0.02 at the 50th, 0.29 ± 0.04 at the 75th, and 0.26 ± 0.08 at the 90th percentile of the PAI-1 distribution, and when estimated from β (p = 6.5x10 ). There was no significant evidence for quantile-specific heritability for factor VII (p = 0.35), D-dimer (p = 0.08), tPA (p = 0.74), or von Willebrand factor (p = 0.79).
Higher mean plasma PAI-1 antigen concentrations tend to accentuate genetic effects (quantile-dependent expressivity), which is consistent with the greater reported differences in PAI-1 concentrations between rs1799889 SERPINE1 (4G/5G) genotypes in patients with osteonecrosis, meningococcal sepsis, obesity, prior myocardial infarction, deep vein thrombosis, and polycystic ovarian syndrome than in healthy controls. It is also consistent with the greater increases in PAI-1 concentrations in 4G-allele carriers than 5G/5G homozygotes following fibrinolytic treatment, low-salt intake, and high saturated fat intake.
纤溶酶原激活物抑制剂-1（PAI-1，又名SERPINE1）是一种具有中度遗传性的糖蛋白，可调节纤维蛋白凝块溶解（纤维蛋白溶解）。
测试PAI-1和其他止血因子的遗传力（h²）在其整个分布范围内是否恒定，或者它们是否是分位数特异性的（即，根据其浓度高低，h²较大或较小）。
对弗雷明汉心脏研究中的5606对亲子对和5310对同胞进行分位数回归。分位数特异性遗传力通过亲子回归斜率（β，h² = 2β /(1 + r)）和同胞回归斜率（β，h² = {(1 + 8rβ) - 1}/(2r)）进行估计。
根据β估计，随着后代年龄和性别调整后的PAI-1分布百分位数增加，遗传力（h² ± SE）显著增加（p = 0.0001）：PAI-1分布的第10百分位数为0.09 ± 0.02，第25百分位数为0.09 ± 0.02，第50百分位数为0.16 ± 0.02，第75百分位数为0.29 ± 0.04，第90百分位数为0.26 ± 0.08；根据β估计时（p = 6.5x10）。对于因子VII（p = 0.35）、D-二聚体（p = 0.08）、组织型纤溶酶原激活剂（tPA，p = 0.74）或血管性血友病因子（p = 0.79），没有显著证据表明存在分位数特异性遗传力。
较高的平均血浆PAI-1抗原浓度往往会增强遗传效应（分位数依赖性表达），这与报道的骨坏死患者rs1799889 SERPINE1（4G/5G）基因型之间PAI-1浓度差异大于健康对照一致，在脑膜炎球菌败血症、肥胖、既往心肌梗死、深静脉血栓形成和多囊卵巢综合征患者中也是如此。这也与纤维蛋白溶解治疗、低盐摄入和高饱和脂肪摄入后4G等位基因携带者的PAI-1浓度增加幅度大于5G/5G纯合子一致。
