Common polymorphisms in angiogenesis

Abstract

A wide variety of diseases have a significant genetic component, including major causes of morbidity and mortality in the western world. Many of these diseases are also angiogenesis dependent. In humans, common polymorphisms, although more subtle in effect than rare mutations that cause Mendelian disease, are expected to have greater overall effects on human disease. Thus, common polymorphisms in angiogenesis-regulating genes may affect the response to an angiogenic stimulus and thereby affect susceptibility to or progression of such diseases. Candidate gene studies have identified several associations between angiogenesis gene polymorphisms and disease. Similarly, emerging pharmacogenomic evidence indicates that several angiogenesis-regulating polymorphisms may predict response to therapy. In contrast, genome-wide association studies have identified only a few risk alleles in obvious angiogenesis genes. As in other traits, regulatory polymorphisms appear to dominate the landscape of angiogenic responsiveness. Rodent assays, including the mouse corneal micropocket assay, tumor models, and a macular degeneration model have allowed the identification and comparison of loci that directly affect the trait. Complementarity between human and animal approaches will allow increased understanding of the genetic basis for angiogenesis-dependent disease.

Figure 1.

VEGF gene polymorphisms. The VEGF gene and surrounding sequence are outlined. Each + represents a polymorphic site. The position of the full-length transcript, exons, and longest splice form are diagrammed. The position of commonly assessed polymorphisms according to both of the commonly used numbering schemes (from the transcription start point “mRNA,” and from the translation start point “ATG”) are indicated. The three major regions of linkage disequilibrium are shown, together with common haplotypes. The haplotype numbering schemes of Stevens (s) (Stevens et al. 2003), Awata (a) (Awata et al. 2005), Garcia-Closas (g) (Garcia-Closas et al. 2007), and McKay (m) (McKay et al. 2009) are indicated, as well as the frequency of the haplotypes in the indicated control populations. Shaded genotypes indicate a difference with the chimpanzee or orangutan genome, suggesting that the shaded allele is the derived allele. The position of the 936C > T polymorphism in the 3′ UTR is also indicated.