Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis

Tgfbm1 (chromosome 5, P = 8 × 10−5) and Tgfbm3 (chromosome 12, P = 6 × 10−11) were identified as loci that modify developmental angiogenesis of Tgfb1−/− mice. Congenic mice validated these loci and demonstrated epistatic interaction between them. The novel locus, Tgfbm3, encompasses ∼22 genes, colocalizes with both tumor susceptibility and atherosclerosis susceptibility loci, and is enriched in genes regulating cell growth and morphogenesis. The use of gene knockout and/or transgenic mice that predispose to a complex trait, such as vascular development/angiogenesis, facilitates the identification of modifiers by simplifying genetic analysis. Identification of genes that modify response to lack of transforming growth factor β1 (TGFβ1) will enhance the understanding of TGFβ1 action in vivo and may help predict which patients would respond well to anti-TGFβ therapy. Identification of angiogenesis-modifying genes may provide new targets for angiogenesis therapies and analysis of polymorphisms therein may contribute to assessment of risk for diseases involving angiogenesis.