Hypoxia‐inducible factor‐1α (HIF‐1α) gene polymorphisms, circulating insulin‐like growth factor binding protein (IGFBP)‐3 levels and prostate cancer

Abstract

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. 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. 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. 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.