内皮生长因子的全基因组关联研究
Genome-wide association study for endothelial growth factors.
作者信息
Lieb Wolfgang, Chen Ming-Huei, Larson Martin G, Safa Radwan, Teumer Alexander, Baumeister Sebastian E, Lin Honghuang, Smith Holly M, Koch Manja, Lorbeer Roberto, Völker Uwe, Nauck Matthias, Völzke Henry, Wallaschofski Henri, Sawyer Douglas B, Vasan Ramachandran S
机构信息
From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.)
From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
出版信息
Circ Cardiovasc Genet. 2015 Apr;8(2):389-97. doi: 10.1161/CIRCGENETICS.114.000597. Epub 2014 Dec 31.
BACKGROUND
Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown.
METHODS AND RESULTS
We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P=2.40×10(-65) [rs2273720] and 3.64×10(-19) [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05×10(-8) in Framingham Heart Study and 8.39×10(-5) in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P=1.84×10(-33) in Framingham Heart Study; P=2.53×10(-30) in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07×10(-8) in Framingham Heart Study; P=0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels.
CONCLUSIONS
Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.
背景
包括血管生成素-2（Ang-2）、其可溶性受体Tie-2（sTie-2）和肝细胞生长因子在内的内皮生长因子在血管生成、血管重塑、局部肿瘤生长以及各种癌症的转移潜能中发挥着重要作用。这些生物标志物的循环水平具有遗传成分（在13%至56%之间），但影响这些生物标志物水平的潜在基因变异在很大程度上尚不清楚。
方法与结果
我们对3571名弗雷明汉心脏研究参与者的循环Ang-2、sTie-2和肝细胞生长因子进行了全基因组关联研究，并在3184名波美拉尼亚健康研究参与者中评估了Ang-2和sTie-2的顶级关联位点的重复性。在多变量调整模型中，sTie-2和肝细胞生长因子浓度与编码各自生物标志物的基因中的单核苷酸多态性相关（顶级P值分别为2.40×10⁻⁶⁵ [rs2273720] 和3.64×10⁻¹⁹ [rs5745687]）。同样，MCPH1基因（Ang-2基因嵌入其中）中的rs2442517与Ang-2水平相关（在弗雷明汉心脏研究中P = 5.05×10⁻⁸，在波美拉尼亚健康研究中P = 8.39×10⁻⁵）。此外，AB0基因中的单核苷酸多态性与sTie-2（顶级单核苷酸多态性rs8176693在弗雷明汉心脏研究中P = 1.84×10⁻³³；在波美拉尼亚健康研究中P = 2.53×10⁻³⁰）和Ang-2（rs8176746在弗雷明汉心脏研究中P = 2.07×10⁻⁸；在波美拉尼亚健康研究中P = 0.001）水平在全基因组显著水平上相关。顶级基因位点解释了生物标志物水平个体间变异的1.7%（Ang-2）至11.2%（sTie-2）。
结论
基因变异导致生长因子水平的个体间变异，并解释了循环肝细胞生长因子、Ang-2和Tie-2的适度比例。这可能潜在地导致家族性癌症易感性，这一前提值得进一步研究。
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