Coen Herak Désirée, Lenicek Krleza Jasna, Radic Antolic Margareta, Horvat Ivana, Djuranovic Vlasta, Zrinski Topic Renata, Zadro Renata
1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia.
2 Department of Laboratory Diagnostics, Children's Hospital Zagreb, Zagreb, Croatia.
Clin Appl Thromb Hemost. 2017 Nov;23(8):1042-1051. doi: 10.1177/1076029616672584. Epub 2016 Oct 18.
Despite the identification of a wide range of inherited and acquired risk factors for arterial ischemic stroke (AIS) in children, genetic risk factors are incompletely characterized and may vary among different populations. We investigated the role of individual and combined inherited prothrombotic and intermediate-risk factors in 73 children with perinatal (n = 35) and childhood AIS (n = 38) and 100 age- and sex-matched controls. Ten polymorphisms in 8 candidate genes encoding coagulation and fibrinolytic proteins (factor V [FV] Leiden, FV HR2, factor II [FII] G20210A, β-fibrinogen [β-FBG]-455G>A, factor XIII [FXIII]-A p.Val34Leu, plasminogen activator inhibitor 1 4G/5G), homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR] C677T, MTHFR A1298C), and intermediate-risk factors (angiotensin-converting enzyme I/D, apoE ∊2-4) were detected using a multilocus genotyping assay. Allele-specific polymerase chain reaction was used for the determination of human platelet alloantigens (HPA-1, HPA-2, HPA-3, and HPA-5). Factor V Leiden was associated with an increased risk of AIS (odds ratio [OR]: 4.72, 95% confidence interval [CI]: 1.22-18.27) and perinatal AIS (OR: 8.29, 95% CI: 1.95-35.24). Human platelet antigen-3b allele carriers had a 2-fold lower risk of AIS (OR: 0.51, 95% CI: 0.26-0.98) and perinatal AIS (OR: 0.40, 95% CI: 0.18-0.92). A 2.21-fold increased risk of childhood AIS (95% CI: 1.03-4.73) was identified in FXIII-A Leu34 allele carriers. Combined FV Leiden/FV HR2, FV Leiden/MTHFR A1298C, FV Leiden/MTHFR C677T/MTHFR A1298C, and FV Leiden/FV HR2/MTHFR A1298C heterozygosity was identified in children with AIS but not in controls, which revealed a statistically significant difference. This case-control study shows that besides already documented association between FV Leiden and AIS, other previously unreported polymorphisms (FXIII-A p.Val34Leu, HPA-3) and several genotype combinations that always include heterozygous FV Leiden can be related to AIS in Croatian population.
尽管已确定儿童动脉缺血性卒中（AIS）存在多种遗传和后天危险因素，但遗传危险因素的特征尚未完全明确，且在不同人群中可能存在差异。我们调查了73例围产期（n = 35）和儿童期AIS（n = 38）患儿以及100例年龄和性别匹配的对照中个体及合并的遗传性血栓前状态和中度危险因素的作用。使用多位点基因分型检测法检测了编码凝血和纤溶蛋白的8个候选基因（凝血因子V [FV] Leiden、FV HR2、凝血因子II [FII] G20210A、β - 纤维蛋白原 [β - FBG] - 455G>A、凝血因子XIII [FXIII] - A p.Val34Leu、纤溶酶原激活物抑制剂1 4G/5G）、同型半胱氨酸代谢（亚甲基四氢叶酸还原酶 [MTHFR] C677T、MTHFR A1298C）以及中度危险因素（血管紧张素转换酶I/D、载脂蛋白E ∊2 - 4）中的10个多态性位点。采用等位基因特异性聚合酶链反应测定人类血小板同种抗原（HPA - 1、HPA - 2、HPA - 3和HPA - 5）。FV Leiden与AIS风险增加相关（比值比 [OR]：4.72，95%置信区间 [CI]：1.22 - 18.27）以及围产期AIS（OR：8.29，95% CI：1.95 - 35.24）。人类血小板抗原 - 3b等位基因携带者发生AIS的风险降低2倍（OR：0.51，95% CI：0.26 - 0.98）以及围产期AIS（OR：0.40，95% CI：0.18 - 0.92）。FXIII - A Leu34等位基因携带者发生儿童期AIS的风险增加2.21倍（95% CI：1.03 - 4.73）。在AIS患儿中发现了合并的FV Leiden/FV HR2、FV Leiden/MTHFR A1298C、FV Leiden/MTHFR C677T/MTHFR A1298C以及FV Leiden/FV HR2/MTHFR A1298C杂合性，而在对照组中未发现，差异具有统计学意义。这项病例对照研究表明，除了已记录的FV Leiden与AIS之间的关联外，其他先前未报道的多态性（FXIII - A p.Val34Leu、HPA - 3）以及几种总是包含FV Leiden杂合子的基因型组合可能与克罗地亚人群的AIS有关。
