☆ 3.8 Article

Genome-Wide Association Study for Endothelial Growth Factors

CIRCULATION-CARDIOVASCULAR GENETICS (2015)

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CIRCULATION-CARDIOVASCULAR GENETICS
卷 8, 期 2, 页码 389-+

出版社

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.114.000597

关键词

angiopoietin-2; endothelial growth factors; genetics; Genome-Wide Association Study; hepatocyte growth factor; Tie-2 receptor

类别

Cardiac & Cardiovascular Systems Genetics & Heredity

资金

  1. National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]
  2. Affymetrix, Inc [N02-HL-6-4278]
  3. National Heart, Lung, and Blood Institute [2K24HL04334, RO1HL080124, RO1HL077477, R01HL093328]
  4. Federal State of Mecklenburg-West Pomerania
  5. University Medicine Greifswald
  6. Siemens Healthcare, Erlangen, Germany
  7. Federal State of Mecklenburg, West Pomerania
  8. German Federal Ministry of Education and Research
  9. 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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