Identification of Association of Common AGGF1 Variants with Susceptibility for Klippel‐Trenaunay Syndrome Using the Structure Association Program

Abstract

SummaryKlippel-Trenaunay syndrome (KTS) is a severe congenital disorder characterized by capillary malformations, venous malformations or varicose veins, and hypertrophy of the affected tissues. The angiogenic factor gene AGGF1 was previously identified as a candidate susceptibility gene for KTS, but further genetic studies are needed to firmly establish the genetic relationship between AGGF1 and KTS. We analyzed HapMap data and identified two tagSNPs, rs13155212 and rs7704267 that capture information for all common variants in AGGF1. The two SNPs were genotyped in 173 Caucasian KTS patients and 477 Caucasian non-KTS controls, and both significantly associated with susceptibility for KTS (P = 0.004 and 0.013, respectively). Permutation testing also showed a significant empirical P value for the association (empirical P = 0.006 and 0.015, respectively). To control for potential confounding due to population stratification, the population structure for both cases and controls was characterized by genotyping of 38 ancestry-informative markers (AIMs) and the STRUCTURE program. The association between the AGGF1 SNPs and KTS remained significant after multivariate analysis by incorporating the inferred cluster scores as a covariate or after removal of outlier individuals identified by STRUCTURE. These results suggest that common AGGF1 variants confer risk of KTS.

Novel Roles of GATA1 in Regulation of Angiogenic Factor AGGF1 and Endothelial Cell Function

“…Tissue immunostaining studies with an anti-AGGF1 antibody identified strong AGGF1 protein expression in blood * This study was supported in part by a Scott Hamilton CARES research grant vessels embedded in various tissues including the heart, kidney, tail, and limb and co-localized with an endothelial specific marker CD31 as well as a vascular smooth muscle cell-specific marker, smooth muscle cell ␣-actin (1). In a small case control study, the frequency of a single nucleotide polymorphism (SNP) in AGGF1, E133K, was found to be greater in cases (3.8%) than in controls (1), but later studies found that E133K showed a frequency of 2.2-3.3% in other general control populations (6,11,12). These results argue that SNP E133K is unlikely to confer a risk of KTS.…”

“…KTS is a congenital disorder, but most cases are sporadic. The genetic basis of KTS is complex and may involve multiple genes, environmental factors, and their interactions (6). To date, identification of susceptibility genes associated with KTS has relied upon gross cytogenetic defects reported in KTS patients.…”

“…These results argue that SNP E133K is unlikely to confer a risk of KTS. On the other hand, a recent large scale case control study employing a STRUCTURE program demonstrates that two common SNPs in AGGF1, exonic SNP rs7704267 and intronic SNP rs13155212, are significantly associated with susceptibility of KTS even after adjustment of population structural parameters of the cases and controls (6). Therefore, AGGF1 remains a strong candidate gene associated with risk of KTS.…”

Aggf1 acts at the top of the genetic regulatory hierarchy in specification of hemangioblasts in zebrafish

“…8,15,16 Aggf1 encodes an interesting angiogenic factor with G-Patch and FHA domains and is associated with increased susceptibility for the vascular disease Klippel-Trenaunay syndrome. [27][28][29] Similar to the vascular endothelial growth factor (VEGF) A, purified wild-type AGGF1 protein promoted strong angiogenesis. 27 Recently, we demonstrated that aggf1 plays an important role in the specification of veins and angiogenesis by activating the AKT signaling pathway in zebrafish embryogenesis.…”

Klippel Trenaunay Syndrome : A Case Report

“…3:q13) has also been reported (Wang et al, 2001). (8) Most cases of KTS are sporadic. But there are certain cases reported which suggests an autosomal dominant pattern of inheritance.…”