Genome-Wide Association Study for Endothelial Growth Factors. (April 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Circulation. Volume 8:Number 2(2015)
• Publication Date: 2015-04
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.114.000597
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>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 <italic>P</italic>=2.40×10<sup>−65</sup> [rs2273720] and 3.64×10<sup>−19</sup> [rs5745687], respectively). Likewise, rs2442517 in the <italic>MCPH1</italic> gene (in which the <italic>Ang-2</italic> gene is embedded) was associated with Ang-2 levels (<italic>P</italic>=5.05×10<sup>−8</sup> in Framingham Heart Study and 8.39×10<sup>−5</sup> in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the <italic>AB0</italic> gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with <italic>P</italic>=1.84×10<sup>−33</sup> in Framingham Heart Study; <italic>P</italic>=2.53×10<sup>−30</sup> in Study of Health in Pomerania) and Ang-2 (rs8176746 with <italic>P</italic>=2.07×10<sup>−8</sup> in Framingham Heart Study; <italic>P</italic>=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.</p> </sec> <sec> <title>Conclusions—</title> <p>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.</p> </sec> </abstract>