Hypoxia-inducible factor-1alpha (HIF-1alpha) gene polymorphisms, circulating insulin-like growth factor binding protein (IGFBP)-3 levels and prostate cancer.
BACKGROUND
The Hypoxia-inducible factor-1 (HIF-1) plays an important role in regulating angiogenesis in response to hypoxia. Two non-synonymous polymorphisms (P582S C-->T and A588T G-->A) in the coding region of the subunit 1alpha (HIF-1alpha) gene have been associated with enhanced stability of the protein and androgen-independent prostate cancer (CaP). Insulin-like growth factor binding protein (IGFBP)-3 mRNA is more abundantly expressed in hypoxia-related inflammatory angiogenesis and recent in vivo data suggest that IGFBP-3 has direct, IGF-independent inhibitory effects on angiogenesis.


METHODS
We examined the association of these polymorphisms with CaP among 1,072 incident cases and 1,271 controls, and further explored their joint associations with various prediagnostic plasma vascular endothelial growth factor (VEGF), IGF-I, and IGFBP-3 levels.


RESULTS
Neither the P582S nor the A588T polymorphism was associated with risk of overall or metastatic/fatal CaP. However, we found that, among men with the homozygous CC wild-type (but not CT/TT) of the HIF-1alpha P582S, higher IGFBP-3 levels (>/= vs. <median) were associated with a 28% (95% CI, 0.55-0.95; P(interaction) = 0.01) lower risk of overall CaP and a 53% (0.25-0.88; P(interaction) = 0.11) lower risk of metastatic and fatal CaP. The A588T polymorphism was too rare to assess interactions.


CONCLUSIONS
The two HIF-1alpha gene polymorphisms were not directly associated with CaP, but the interaction between the P582S polymorphism and IGFBP-3 merits further evaluation in mechanistic studies.
Li
Haojie
H
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. haojie.li@channing.harvard.edu
Bubley
Glenn J
GJ
Balk
Stephen P
SP
Gaziano
J Michael
JM
Pollak
Michael
M
Stampfer
Meir J
MJ
Ma
Jing
J
D000368:Aged; D016022:Case-Control Studies; D004273:DNA, Neoplasm / Q000235:genetics; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D009389:Neovascularization, Pathologic / Q000097:blood / Q000235:genetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood / Q000098:blood supply / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D004273:DNA, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I