TY - JOUR
T1 - Genome-Wide Association Study for Endothelial Growth Factors
AU - Lieb, Wolfgang
AU - Chen, Ming Huei
AU - Larson, Martin G.
AU - Safa, Radwan
AU - Teumer, Alexander
AU - Baumeister, Sebastian E.
AU - Lin, Honghuang
AU - Smith, Holly M.
AU - Koch, Manja
AU - Lorbeer, Roberto
AU - Völker, Uwe
AU - Nauck, Matthias
AU - Völzke, Henry
AU - Wallaschofski, Henri
AU - Sawyer, Douglas B.
AU - Vasan, Ramachandran S.
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/4/4
Y1 - 2015/4/4
N2 - 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.
AB - 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.
KW - Genome-Wide Association Study
KW - Tie-2 receptor
KW - angiopoietin-2
KW - endothelial growth factors
KW - genetics
KW - hepatocyte growth factor
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U2 - 10.1161/CIRCGENETICS.114.000597
DO - 10.1161/CIRCGENETICS.114.000597
M3 - Article
C2 - 25552591
AN - SCOPUS:84942940724
SN - 1942-325X
VL - 8
SP - 389
EP - 397
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 2
ER -