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

Authors

  • Y. Hu,

    1. Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Tausig Cancer Center, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
    2. Y. H. and L. L contributed equally to this work
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  • L. Li,

    1. Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Tausig Cancer Center, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
    2. Y. H. and L. L contributed equally to this work
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  • S. B. Seidelmann,

    1. Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Tausig Cancer Center, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
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  • A. A. Timur,

    1. Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Tausig Cancer Center, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
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  • P. H. Shen,

    1. Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, MD 20892, USA
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  • D. J. Driscoll,

    1. Department of Pediatrics, Mayo Clinic, Rochester, MN, USA
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  • Q. K. Wang

    Corresponding author
    1. Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Tausig Cancer Center, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
    2. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, P. R. China
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*Corresponding author: Qing Kenneth Wang, Center for Cardiovascular Genetics/NE4–202, Cleveland Clinic, Cleveland, Cleveland, OH 44195, USA. Tel: 001 216 445 0570. Fax: 001 216 636 1231. E-mail: wangq2@ccf.org

Summary

Klippel-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.

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