Mansvelt E P, Laffan M, McVey J H, Tuddenham E G
Haemostasis Research Group, MRC Clinical Sciences Centre, ICSM, London, UK.
Thromb Haemost. 1998 Oct;80(4):561-5.
High FVIII:C levels have previously been shown to be an independent risk factor for thrombosis with 4.8 times higher potential risk of thrombosis in individuals with FVIII:C levels greater than 1.5 u/ml. Recently, we found that raised FVIII:C levels are largely attributable to elevated FVIII:Ag levels. The determinants of FVIII:Ag levels are unclear and might be partly genetic. The promoter of the F8 gene has recently been characterised we therefore investigated the promoter and the 3' terminus of the F8 gene for possible polymorphisms associated with raised FVIII:Ag levels in 62 selected individuals with a thrombotic tendency. We confirm previous reports that raised FVIII:C levels are largely attributable to an elevation in FVIII:Ag and this is also associated with elevation of vWF; non-O blood group: relatively short APTT and relatively low APC ratio. We screened 1140 bp of the proximal promoter including the protein binding sites identified by DNase I footprint analysis by SSCP, however no polymorphisms were identified. Direct DNA sequence analysis of the region -542 to +165 failed to identify any sequence polymorphisms. The recently described polymorphism in the polyadenylation cleavage site in the prothrombin gene associated with increased prothrombin activity prompted us to screen the region surrounding the 3' terminus of the F8 gene for polymorphisms but we found none.
此前研究表明，FVIII:C水平升高是血栓形成的独立危险因素，FVIII:C水平高于1.5 u/ml的个体发生血栓的潜在风险高4.8倍。最近，我们发现FVIII:C水平升高在很大程度上归因于FVIII:Ag水平升高。FVIII:Ag水平的决定因素尚不清楚，可能部分与基因有关。F8基因的启动子最近已被鉴定，因此我们在62名有血栓形成倾向的选定个体中，研究了F8基因的启动子和3'末端，以寻找与FVIII:Ag水平升高相关的可能多态性。我们证实了之前的报道，即FVIII:C水平升高在很大程度上归因于FVIII:Ag升高，这也与vWF升高、非O血型、相对较短的活化部分凝血活酶时间（APTT）和相对较低的活化蛋白C比值有关。我们通过单链构象多态性（SSCP）筛选了近端启动子的1140 bp，包括通过DNA酶I足迹分析确定的蛋白结合位点，但未发现多态性。对-542至+165区域的直接DNA序列分析未能鉴定出任何序列多态性。凝血酶原基因多聚腺苷酸化切割位点最近描述的多态性与凝血酶原活性增加有关，这促使我们筛选F8基因3'末端周围区域的多态性，但未发现任何多态性。
