Genetics, epigenetics and pharmaco-(epi)genomics

Introduction Angiogenesis is genetically pre-determined Mutations causing vascular anomalies Venous anomalies Haemangiomas The transforming growth factor-ss in vascular anomalies Cerebral cavernous malformations Translocations reveal novel angiogenic genes Single nucleotide polymorphisms shape the angio-genome SNPs in VEGF and their association with cancer SNPs in VEGF pathway genes associated with other diseases Genetic variability in VEGFR-2 Genetic variability in HIF-1 alpha SNPs in VEGFR-1 integrate angiogenesis within the P53 pathway Variations in angiogenic genes are linked with neurodegeneration Angiogenic factors in genome-wide association studies Copy number variability affects angiogenesis Epigenetic regulation of angiogenesis Methylation of anti-angiogenic factors Methylation as a second hit event in cancer Histone modifications determine angiogenesis Micromanagers of angiogenesis Perspectives Angiogenesis is controlled by a balance between pro- and anti-angiogenic factors. Studies in mice and human beings have shown that this balance, as well as the general sensitivity of the endothelium to these factors, is genetically pre-determined. In an effort to dissect this genetic basis, different types of genetic variability have emerged: mutations and translocations in angiogenic factors have been linked to several vascular malformations and haemangiomas, whereas SNPs have been associated with complex genetic disorders, such as cancer, neurodegeneration and diabetes. In addition, copy number alterations of angiogenic factors have been reported in several tumours. More recently, epigenetic changes caused by aberrant DNA methylation or histone acetylation of anti-angiogenic molecules have been shown to determine angiogenesis as well. Initial studies also revealed a crucial role for microRNAs in stimulating or reducing angiogenesis. So far, most of these genetic studies have focused on tumour angiogenesis, but future research is expected to improve our understanding of how genetic variants determine angiogenesis in other diseases. Importantly, these genetic insights might also be of important clinical relevance for the use of anti-angiogenic strategies in cancer or macular degeneration.