Genome-wide association study for endothelial growth factors.

Abstract

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.

• Authors: Wolfgang Lieb, Ming-Huei Chen, Martin G Larson, Radwan Safa, Alexander Teumer, Sebastian E Baumeister, Honghuang Lin, Holly M Smith, Manja Koch, Roberto Lorbeer, Uwe Völker, Matthias Nauck, Henry Völzke, Henri Wallaschofski, Douglas B Sawyer, Ramachandran S Vasan
• Journal: Circulation. Cardiovascular genetics (Circ Cardiovasc Genet) Vol. 8 Issue 2 Pg. 389-97 (Apr 2015) ISSN: 1942-3268 [Electronic] United States
• PMID: 25552591 (Publication Type: Clinical Study, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• HGF protein, human
• VPS51 protein, human
• Vesicular Transport Proteins
• Hepatocyte Growth Factor
• Receptor, TIE-2

Topics

• Adult
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Hepatocyte Growth Factor (genetics)
• Humans
• Male
• Middle Aged
• Models, Genetic
• Neoplasms (genetics)
• Polymorphism, Single Nucleotide
• Receptor, TIE-2 (genetics)
• Vesicular Transport Proteins (genetics)