Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 8, Issue 2, Pages 389-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.114.000597
Keywords
angiopoietin-2; endothelial growth factors; genetics; Genome-Wide Association Study; hepatocyte growth factor; Tie-2 receptor
Funding
- National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc [N02-HL-6-4278]
- National Heart, Lung, and Blood Institute [2K24HL04334, RO1HL080124, RO1HL077477, R01HL093328]
- Federal State of Mecklenburg-West Pomerania
- University Medicine Greifswald
- Siemens Healthcare, Erlangen, Germany
- Federal State of Mecklenburg, West Pomerania
- German Federal Ministry of Education and Research
- Ministry of Cultural Affairs of the German Federal State of Mecklenburg, West Pomerania [03IS2061A]
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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=2.40x10(-65) [rs2273720] and 3.64x10(-19) [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05x10(-8) in Framingham Heart Study and 8.39x10(-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=1.84x10(-33) in Framingham Heart Study; P=2.53x10(-30) in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07x10(-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.
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