ADRBD1 (GRK2), TBXA2R and VEGFA rSNPs in KLF4 and SP1 TFBS Exhibit Linkage Disequilibrium


The adrenergic receptor kinase 1 (ADRBK1), thromboxane A2 receptor (TBXA2R) and vascular endothelial growth factor (VEGFA) regulatory (r) single nucleotide polymorphisms (SNPs) found in the potential stimulating protein-1 (SP1) and Kruppel-like factor-4 (KLF4) transcriptional factor binding sites (TFBS) within these genes are in linkage disequilibrium (LD). The LD may result from rSNP alleles that create TFBS for the KLF4 and SP1 transcriptional factors (TF) since the alternate rSNP alleles do not create these TFBS. Consequently, haplotypes carrying the rSNP alleles that create KLF4 and SP1 TFBS are essential for ADRBK1, TBXA2R and VEGFA gene regulation by these TFs.

Share and Cite:

Buroker, N. (2014) ADRBD1 (GRK2), TBXA2R and VEGFA rSNPs in KLF4 and SP1 TFBS Exhibit Linkage Disequilibrium. Open Journal of Genetics, 4, 183-189. doi: 10.4236/ojgen.2014.43019.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Nemer, M. and Horb, M.E. (2007) The KLF Family of Transcriptional Regulators in Cardiomyocyte Proliferation and Differentiation. Cell Cycle, 6, 117-121.
[2] Liu, Y., Zhang, C., Fan, J., Xiao, L., Yin, B., Zhou, L. and Xia, S. (2011) Comprehensive Analysis of Clinical Significance of Stem-Cell Related Factors in Renal Cell Cancer. World Journal of Surgical Oncology, 9, 121.
[3] Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. and Yamanaka, S. (2007) Induction of Pluripotent Stem Cells from Adult human Fibroblasts by Defined Factors. Cell, 131, 861-872.
[4] Suzuki, T., Aizawa, K., Matsumura, T. and Nagai, R. (2005) Vascular Implications of the Kruppel-Like Family of Transcription Factors. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 1135-1141.
[5] Kalra, I.S., Alam, M.M., Choudhary, P.K. and Pace, B.S. (2011) Kruppel-Like Factor 4 Activates HBG Gene Expression in Primary Erythroid Cells. British Journal of Haematology, 154, 248-259.
[6] Shi, J.H., Zheng, B., Chen, S., Ma, G.Y. and Wen, J.K. (2012) Retinoic Acid Receptor Alpha Mediates All-Trans Retinoic Acid-Induced Klf4 Gene Expression by Regulating Klf4 Promoter Activity in Vascular Smooth Muscle Cells. The Journal of Biological Chemistry, 287, 10799-10811.
[7] Evans, P.M. and Liu, C. (2008) Roles of Krupel-Like Factor 4 in Normal Homeostasis, Cancer and Stem Cells. Acta Biochimica et Biophysica Sinica, 40, 554-564.
[8] Zhang, X.H., Zheng, B., Gu, C., Fu, J.R. and Wen, J.K. (2012) TGF-beta1 Downregulates AT1 Receptor Expression via PKC-Delta-Mediated Sp1 Dissociation from KLF4 and Smad-Mediated PPAR-Gamma Association with KLF4. Arteriosclerosis, Thrombosis, and Vascular Biology, 32, 1015-1023.
[9] Penn, R.B. and Benovic, J.L. (1994) Structure of the Human Gene Encoding the Beta-Adrenergic Receptor Kinase. The Journal of Biological Chemistry, 269, 14924-14930.
[10] Gannon, A.M. and Kinsella, B.T. (2008) Regulation of the Human Thromboxane A2 Receptor Gene by Sp1, Egr1, NF-E2, GATA-1, and Ets-1 in Megakaryocytes. The Journal of Lipid Research, 49, 2590-2604.
[11] Gannon, A.M., Turner, E.C., Reid, H.M. and Kinsella, B.T. (2009) Regulated Expression of the Alpha Isoform of the Human Thromboxane A2 Receptor during Megakaryocyte Differentiation: A Coordinated Role for WT1, Egr1, and Sp1. Journal of Molecular Biology, 394, 29-45.
[12] Abdelrahim, M., Smith 3rd, R., Burghardt, R. and Safe, S. (2004) Role of Sp Proteins in Regulation of Vascular Endothelial Growth Factor Expression and Proliferation of Pancreatic Cancer Cells. Cancer Research, 64, 6740-6749.
[13] Knight, J.C. (2003) Functional Implications of Genetic Variation in Non-Coding DNA for Disease Susceptibility and Gene Regulation. Clinical Science, 104, 493-501.
[14] Knight, J.C. (2005) Regulatory Polymorphisms Underlying Complex Disease Traits. Journal of Molecular Medicine, 83, 97-109.
[15] Wang, X., Tomso, D.J., Liu, X. and Bell, D.A. (2005) Single Nucleotide Polymorphism in Transcriptional Regulatory Regions and Expression of Environmentally Responsive Genes. Toxicology and Applied Pharmacology, 207, 84-90.
[16] Wang, X., Tomso, D.J., Chorley, B.N., Cho, H.Y., Cheung, V.G., Kleeberger, S.R. and Bell, D.A. (2007) Identification of Polymorphic Antioxidant Response Elements in the Human Genome. Human Molecular Genetics, 16, 1188-1200.
[17] Claessens, F., Verrijdt, G., Schoenmakers, E., Haelens, A., Peeters, B., Verhoeven, G. and Rombauts, W. (2001) Selective DNA Binding by the Androgen Receptor as a Mechanism for Hormone-Specific Gene Regulation. The Journal of Steroid Biochemistry and Molecular Biology, 76, 23-30.
[18] Hsu, M.H., Savas, U., Griffin, K.J. and Johnson, E.F. (2007) Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-Binding Protein and Lovastatin. The Journal of Biological Chemistry, 282, 5225-5236.
[19] Takai, H., Araki, S., Mezawa, M., Kim, D.S., Li, X., Yang, L., Li, Z., Wang, Z., Nakayama, Y. and Ogata, Y. (2008) AP1 Binding Site Is Another Target of FGF2 Regulation of Bone Sialoprotein Gene Transcription. Gene, 410, 97-104.
[20] Buroker, N.E., Huang, J.Y., Barboza, J., Ledee, D.R., Eastman Jr., R.J., Reinecke, H., Ning, X.H., Bassuk, J.A. and Portman, M.A. (2012) The Adaptor-Related Protein Complex 2, Alpha 2 Subunit (AP2alpha2) Gene Is a Peroxisome Proliferator-Activated Receptor Cardiac Target Gene. The Protein Journal, 31, 75-83.
[21] Huang, C.N., Huang, S.P., Pao, J.B., Hour, T.C., Chang, T.Y., Lan, Y.H., Lu, T.L., Lee, H.Z., Juang, S.H., Wu, P.P., Huang, C.Y., Hsieh, C.J. and Bao, B.Y. (2012) Genetic Polymorphisms in Oestrogen Receptor-Binding Sites Affect Clinical Outcomes in Patients with Prostate Cancer Receiving Androgen-Deprivation Therapy. Journal of Internal Medicine, 271, 499-509.
[22] Huang, C.N., Huang, S.P., Pao, J.B., Chang, T.Y., Lan, Y.H., Lu, T.L., Lee, H.Z., Juang, S.H., Wu, P.P., Pu, Y.S., Hsieh, C.J. and Bao, B.Y. (2012) Genetic Polymorphisms in Androgen Receptor-Binding Sites Predict Survival in Prostate Cancer Patients Receiving Androgen-Deprivation Therapy. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO, 23, 707-713.
[23] Yu, B., Lin, H., Yang, L., Chen, K., Luo, H., Liu, J., Gao, X., Xia, X. and Huang, Z. (2012) Genetic Variation in the Nrf2 Promoter Associates with Defective Spermatogenesis in Humans. Journal of Molecular Medicine, 2012, 1333-1342.
[24] Wu, J., Richards, M.H., Huang, J., Al-Harthi, L., Xu, X., Lin, R., Xie, F., Gibson, A.W., Edberg, J.C. and Kimberly, R.P. (2011) Human FasL Gene Is a Target of Beta-Catenin/T-Cell Factor Pathway and Complex FasL Haplotypes Alter Promoter Functions. PLoS ONE, 6, e26143.
[25] Alam, M., Pravica, V., Fryer, A.A., Hawkins, C.P. and Hutchinson, I.V. (2005) Novel Polymorphism in the Promoter Region of the Human Nerve Growth-Factor Gene. International Journal of Immunogenetics, 32, 379-382.
[26] Lobmeyer, M.T., Wang, L., Zineh, I., Turner, S.T., Gums, J.G., Chapman, A.B., Cooper-DeHoff, R.M., Beitelshees, A.L., Bailey, K.R., Boerwinkle, E., Pepine, C.J. and Johnson, J.A. (2011) Polymorphisms in Genes Coding for GRK2 and GRK5 and Response Differences in Antihypertensive-Treated Patients. Pharmacogenetics and Genomics, 21, 42-49.
[27] Takeuchi, K., Mashimo, Y., Shimojo, N., Arima, T., Inoue, Y., Morita, Y., Sato, K., Suzuki, S., Nishimuta, T., Watanabe, H., Hoshioka, A., Tomiita, M., Yamaide, A., Watanabe, M., Okamoto, Y., Kohno, Y., Hata, A. and Suzuki, Y. (2013) Functional Variants in the Thromboxane A2 Receptor Gene Are Associated with Lung Function in Childhood-Onset Asthma. Clinical & Experimental Allergy, 43, 413-424.
[28] Buroker, N.E., Ning, X.H., Zhou, Z.N., Li, K., Cen, W.J., Wu, X.F., Zhu, W.Z., Scott, C.R. and Chen, S.H. (2013) VEGFA SNPs and Transcriptional Factor Binding Sites Associated with High Altitude Sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau. The Journal of Physiological Sciences, 63, 183-193.
[29] Bryne, J.C., Valen, E., Tang, M.H., Marstrand, T., Winther, O., da Piedade, I., Krogh, A., Lenhard, B. and Sandelin, A. (2008) JASPAR, the Open Access Database of Transcription Factor-Binding Profiles: New Content and Tools in the 2008 Update. Nucleic Acids Research, 36, D102-D106.
[30] Sandelin, A., Alkema, W., Engstrom, P., Wasserman, W.W. and Lenhard, B. (2004) JASPAR: An Open-Access Database for Eukaryotic Transcription Factor Binding Profiles. Nucleic Acids Research, 32, D91-94.
[31] Sandelin, A., Wasserman, W.W. and Lenhard, B. (2004) ConSite: Web-Based Prediction of Regulatory Elements Using Cross-Species Comparison. Nucleic Acids Research, 32, W249-W252.
[32] Buroker, N.E., Ning, X.H., Zhou, Z.N., Li, K., Cen, W.J., Wu, X.F., Zhu, W.Z., Scott, C.R. and Chen, S.H. (2012) AKT3, ANGPTL4, eNOS3, and VEGFA Associations with High Altitude Sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau. International Journal of Hematology, 96, 200-213.
[33] Brogan, I.J., Khan, N., Isaac, K., Hutchinson, J.A., Pravica, V. and Hutchinson, I.V. (1999) Novel Polymorphisms in the Promoter and 5’ UTR Regions of the Human Vascular Endothelial Growth Factor Gene. Human Immunology, 60, 1245-1249.
[34] Pennisi, E. (2011) The Biology of Genomes. Disease Risk Links to Gene Regulation. Science, 332, 1031.
[35] Kumar, V., Wijmenga, C. and Withoff, S. (2012) From Genome-Wide Association Studies to Disease Mechanisms: Celiac Disease as a Model for Autoimmune Diseases. Seminars in Immunopathology, 34, 567-580.
[36] Hindorff, L.A., Sethupathy, P., Junkins, H.A., Ramos, E.M., Mehta, J.P., Collins, F.S. and Manolio, T.A. (2009) Potential Etiologic and Functional Implications of Genome-Wide Association Loci for Human Diseases and Traits. Proceedings of the National Academy of Sciences of the United States of America, 106, 9362-9367.
[37] Kumar, V., Westra, H.J., Karjalainen, J., Zhernakova, D.V., Esko, T., Hrdlickova, B., Almeida, R., Zhernakova, A., Reinmaa, E., Vosa, U., Hofker, M.H., Fehrmann, R.S., Fu, J., Withoff, S., Metspalu, A., Franke, L. and Wijmenga, C. (2013) Human Disease-Associated Genetic Variation Impacts Large Intergenic Non-Coding RNA Expression. PLoS Genetics, 9, e1003201.
[38] Chorley, B.N., Wang, X., Campbell, M.R., Pittman, G.S., Noureddine, M.A. and Bell, D.A. (2008) Discovery and Verification of Functional Single Nucleotide Polymorphisms in Regulatory Genomic Regions: Current and Developing Technologies. Mutation Research, 659, 147-157.
[39] Prokunina, L. and Alarcon-Riquelme, M.E. (2004) Regulatory SNPs in Complex Diseases: Their Identification and Functional Validation. Expert Reviews in Molecular Medicine, 6, 1-15.
[40] Buckland, P.R. (2006) The Importance and Identification of Regulatory Polymorphisms and Their Mechanisms of Action. Biochimica et Biophysica Acta, 1762, 17-28.
[41] Sadee, W., Wang, D., Papp, A.C., Pinsonneault, J.K., Smith, R.M., Moyer, R.A. and Johnson, A.D. (2011) Pharmacogenomics of the RNA World: Structural RNA Polymorphisms in Drug Therapy. Clinical Pharmacology & Therapeutics, 89, 355-365.
[42] Gaudreault, I., Guay, D. and Lebel, M. (2004) YB-1 Promotes Strand Separation in Vitro of Duplex DNA Containing Either Mispaired Bases or Cisplatin Modifications, Exhibits Endonucleolytic Activities and Binds Several DNA Repair Proteins. Nucleic Acids Research, 32, 316-327.
[43] Joel, P., Shao, W. and Pratt, K. (1993) A Nuclear Protein with Enhanced Binding to Methylated Sp1 Sites in the AIDS Virus Promoter. Nucleic Acids Research, 21, 5786-5793.
[44] Shastry, B.S. (2009) SNPs: Impact on Gene Function and Phenotype. Methods in Molecular Biology, 578, 3-22.
[45] Teng, M., Ichikawa, S., Padgett, L.R., Wang, Y., Mort, M., Cooper, D.N., Koller, D.L., Foroud, T., Edenberg, H.J., Econs, M.J. and Liu, Y. (2012) regSNPs: A Strategy for Prioritizing Regulatory Single Nucleotide Substitutions. Bioinformatics, 28, 1879-1886.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.