Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network. Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel-Trenaunay syndrome (KTS). One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription. The second is mutation E133K identified in five KTS patients, but not in 200 matched controls. VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, and suppression of VG5Q expression inhibits vessel formation. E133K is a functional mutation that substantially enhances the angiogenic effect of VG5Q. VG5Q shows strong expression in blood vessels and is secreted as vessel formation is initiated. VG5Q can bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion. We also demonstrate a direct interaction of VG5Q with another secreted angiogenic factor, TWEAK (also known as TNFSF12). These results define VG5Q as an angiogenic factor, establish VG5Q as a susceptibility gene for KTS, and show that increased angiogenesis is a molecular pathogenic mechanism of KTS.

FOXO1A and FOXO3A are two members of the FoxO family. FOXO3A has recently been linked to human longevity in Japanese, German and Italian populations. Here we tested the genetic contribution of FOXO1A and FOXO3A to the longevity phenotype in Han Chinese population. Six tagging SNPs from FOXO1A and FOXO3A were selected and genotyped in 1817 centenarians and younger individuals. Two SNPs of FOXO1A were found to be associated with longevity in women (P = 0.01-0.005), whereas all three SNPs of FOXO3A were associated with longevity in both genders (P = 0.005-0.001). One SNP from FOXO1A was found not to be associated with longevity. In haplotype association tests, the OR (95% CI) for haplotypes TTG and CCG of FOXO1A in association with female longevity were 0.72 (0.58-0.90) and 1.38 (1.08-1.76), P = 0.0033 and 0.0063, respectively. The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) = 0.67 (0.51-0.86), P = 0.0014; CGT: OR (95% CI) = 1.48 (1.12-1.94), P = 0.0035] and in women [GTC: OR (95% CI) = 0.75 (0.60-0.94), P = 0.0094; CGT: OR (95% CI) = 1.47 (1.16-1.86), P = 0.0009]. The haplotype association tests were validated by permutation analysis. The association of FOXO1A with female longevity was replicated in 700 centenarians and younger individuals that were sampled geographically different from the original population. Thus, we demonstrate that, unlike FOXO3A, FOXO1A is more closely associated with human female longevity, suggesting that the genetic contribution to longevity trait may be affected by genders.

In developing nations, low soil nitrogen (N) availability is a primary limitation to crop production and food security, while in rich nations, intensive N fertilization is a primary economic, energy, and environmental cost to crop production. It has been proposed that genetic variation for root architectural and anatomical traits enhancing the exploitation of deep soil strata could be deployed to develop crops with greater N acquisition. Here, we provide evidence that maize (Zea mays) genotypes with few crown roots (crown root number [CN]) have greater N acquisition from low-N soils. Maize genotypes differed in their CN response to N limitation in greenhouse mesocosms and in the field. Low-CN genotypes had 45% greater rooting depth in low-N soils than high-CN genotypes. Deep injection of (15)N-labeled nitrate showed that low-CN genotypes under low-N conditions acquired more N from deep soil strata than high-CN genotypes, resulting in greater photosynthesis and plant N content. Under low N, low-CN genotypes had greater biomass than high-CN genotypes at flowering (85% in the field study in the United States and 25% in South Africa). In the field in the United States, 1.8× variation in CN was associated with 1.8× variation in yield reduction by N limitation. Our results indicate that CN deserves consideration as a potential trait for genetic improvement of N acquisition from low-N soils.