Hunault M, Arbini A A, Lopaciuk S, Carew J A, Bauer K A
Department of Medicine, Brockton-West Roxbury Department of Veterans Affairs Medical Center, West Roxbury, MA 02132, USA.
Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2825-9. doi: 10.1161/01.atv.17.11.2825.
Factor VII levels are regulated by environmental and genetic factors. Two polymorphisms, a G-to-A transversion at nucleotide 10,976 resulting in Arg353Gln and a decanucleotide insert at position -323 in the 5'-flanking region of the factor VII gene, have been associated with a 20% to 25% reduction in plasma factor VII levels. However Arg353Gln almost always segregates on alleles containing the insert in UK and Italian populations, thereby making it impossible to independently evaluate the impact of Arg353Gln on factor VII levels in these ethnic groups. We have evaluated the influence of genotype on factor VII levels in 99 healthy Polish blood donors and observed that Arg353Gln frequently occurs in the absence of the insert. In univariate analysis, the mean levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) were significantly lower in 16 people who were heterozygous for Arg353Gln and the insert compared with 72 normal subjects who had neither Arg353Gln nor the insert (88.8% of normal and 83.1% versus 102% and 100%, P = .019 and P = .0003, respectively). In nine subjects heterozygous for Arg353Gln alone, VII:C and VII:Ag were significantly decreased compared with the normal subjects (81.9% and 83%, respectively, P = .007 and P = .004). In multivariate analysis, Arg353Gln but not the insert significantly reduced VII:C and VII:Ag after adjustment for age and plasma triglycerides (P < .05 and P = .02, respectively). To evaluate the mechanism responsible for reduced factor VII levels in individuals with Arg353Gln, we performed transient transfection assays with factor VII cDNA containing the base substitution resulting in Gln353 and wild-type factor VII cDNA in COS-1 cells. The levels of VII:Ag in the cell lysates were similar, but the amino acid substitution significantly reduced factor VII secretion into the media to 74.9% of wild-type (P = .0001). Based on these in vivo and in vitro studies, we conclude that the Arg353Gln polymorphism alone can decrease plasma factor VII levels.
凝血因子VII水平受环境和遗传因素调控。两种多态性，即第10976位核苷酸处的G到A颠换导致精氨酸353变为谷氨酰胺（Arg353Gln）以及凝血因子VII基因5'侧翼区 -323位的十核苷酸插入，与血浆凝血因子VII水平降低20%至25%有关。然而，在英国和意大利人群中，Arg353Gln几乎总是与含有该插入序列的等位基因连锁，因此无法独立评估Arg353Gln对这些种族群体中凝血因子VII水平的影响。我们评估了99名健康波兰献血者的基因型对凝血因子VII水平的影响，发现Arg353Gln常出现在无该插入序列的情况下。在单因素分析中，16名Arg353Gln和该插入序列杂合的个体的凝血因子VII凝血活性（VII:C）和凝血因子VII抗原（VII:Ag）平均水平，与72名既无Arg353Gln也无该插入序列的正常受试者相比显著降低（分别为正常水平的88.8%和83.1%，而正常受试者为102%和100%，P = 0.019和P = 0.0003）。在仅为Arg353Gln杂合的9名受试者中，VII:C和VII:Ag与正常受试者相比显著降低（分别为81.9%和83%，P = 0.007和P = 0.004）。在多因素分析中，校正年龄和血浆甘油三酯后，Arg353Gln而非该插入序列显著降低VII:C和VII:Ag（分别为P < 0.05和P = 0.02）。为评估Arg353Gln个体中凝血因子VII水平降低的机制，我们在COS - 1细胞中用含有导致谷氨酰胺353的碱基替换的凝血因子VII cDNA和野生型凝血因子VII cDNA进行了瞬时转染实验。细胞裂解物中VII:Ag水平相似，但氨基酸替换显著降低了凝血因子VII向培养基中的分泌，降至野生型的74.9%（P = 0.0001）。基于这些体内和体外研究，我们得出结论，单独的Arg353Gln多态性可降低血浆凝血因子VII水平。
