High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11
High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11
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DOI：
10.1182/blood-2004-05-2018
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发表时间：
2005-01-15
期刊：
影响因子：
20.3
通讯作者：
Schambeck, CM
中科院分区：
文献类型：
--
作者：
Berger, M;Mattheisen, M;Schambeck, CM
已知高因子VIII（FVIII）水平是深静脉血栓形成的危险因素，但高FVIII水平的机制仍不清楚。在此，定义了一种新的表型“FVIII水平残留”（FVIII-R），以消除常见决定因素对FVIII水平的影响。我们研究了13个家族的血栓形成患者和可重复的高FVIII水平的原因不明。由于家族聚集性很明显，我们寻找可能的遗传基础。用402个均匀分布的微卫星标记进行基因组扫描。使用方差分量法的定量连锁分析显示了FVIII-R与8号染色体上的基因座连锁的暗示性证据（比值对数[LOD] = 2.1）。此外，我们进行了参数探索性连锁分析的二分法FVIII-R，考虑到父母的原产地的影响。单性状位点MOD-评分分析表明，在5号和11号染色体上的印记模型下的连锁的暗示性证据。此外，一个2-traitlocus分析下的乘法模型的5号和11号染色体的位点产生了显着的LOD为4.44。这证实了单性状位点分析在两个位点上都存在父系印记的发现。我们的研究结果表明，静脉血栓栓塞症中的高FVIII水平代表了由几种遗传因素引起的复杂特征。
High factor VIII (FVIII) levels are known to be a risk factor for deep venous thrombosis, but the mechanisms responsible for high FVIII levels remain unclear. Here, a new phenotype "FVIII level residuum" (FVIII-R) was defined in order to eliminate the impact of common determinants on FVIII levels. We studied 13 families of patients with thrombosis and reproducibly high FVIII levels of unknown origin. Since familial clustering was evident, we looked for a possible genetic basis. A genome scan was performed with 402 evenly spaced microsatellite markers. A quantitative linkage analysis using variance component methods showed suggestive evidence for linkage of FVIII-R with a locus on chromosome 8 (logarithm of odds [LOD] = 2.1). In addition, we performed parametric exploratory linkage analysis of dichotomized FVIII-R, taking a parent-of-origin effect into account. Single-trait-locus MOD-score analysis showed suggestive evidence for linkage under an imprinting model at chromosomes 5 and 11. Furthermore, a 2-traitlocus analysis under a multiplicative model for the loci of chromosomes 5 and 11 yielded a remarkable LOD of 4.44. It confirmed the finding of paternal imprinting, obtained by sing le-trait-locus analysis, at both loci. Our results suggest that high FVIII levels in venous thromboembolism represent a complex trait caused by several genetic factors.