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 JBM  Vol.5 No.4 , April 2017
Identifying Changes in Punitive Transcriptional Factor Binding Sites Created by PPARα/δ/γ SNPs Associated with Disease
Abstract: Single nucleotide polymorphisms (SNPs) located in the PPARα/δ/γ genes that have been previously found to be significantly associated with human disease or a condition were also found to alter the genes punitive transcriptional factor binding sites (TFBS). Two alleles (C/G) of the PPARα SNP (rs1800206) were found to generate 7 common and 8 unique punitive TFBS. One of the unique TFBS created by the minor G (0.02) allele is for the T-Box 4 (TBX4) transcription factor which is associated with heritable pulmonary arterial hypertension. Two alleles (A/G) of the PPARδ SNP (rs2016520) were found to generate 20 unique punitive TFBS while the two alleles (C/G) of the PPARδ SNP (rs9794) were found to generate 11 common and 11unique punitive TFBS. The alleles of the PPARγ SNPs (rs10865710, rs12629751, rs709158, rs1805192 and rs3856806) were found to generate 15, 12, 16, 2 and 21 common and 9, 4, 12, 4 and 7 unique punitive TFBS, respectively. These changes in TFBS are discussed with relation to alterations in gene expression that may result in disease or change in human condition.
Cite this paper: Buroker, N. (2017) Identifying Changes in Punitive Transcriptional Factor Binding Sites Created by PPARα/δ/γ SNPs Associated with Disease. Journal of Biosciences and Medicines, 5, 81-100. doi: 10.4236/jbm.2017.54008.
References

[1]   Berger, J. and Moller, D.E (2002) The Mechanisms of Action of PPARs. Annual Review of Medicine, 53, 409-435.
https://doi.org/10.1146/annurev.med.53.082901.104018

[2]   Boitier, E., Gautier, J.C. and Roberts, R. (2003) Advances in Understanding the Regulation of Apoptosis and Mitosis by Peroxisome-Proliferator Activated Receptors in Pre-Clinical Models: Relevance for Human Health and Disease. Comparative Hepatology, 2, 3.

[3]   Harmon, G.S., Lam, M.T. and Glass, C.K. (2011) PPARs and Lipid Ligands in Inflammation and Metabolism. Chemical Reviews, 111, 6321-6340.
https://doi.org/10.1021/cr2001355

[4]   Vitale, S.G., Lagana, A.S., Nigro, A., La Rosa, V.L., Rossetti, P., Rapisarda, A.M., et al. (2016) Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions. PPAR Research, 2016, 651-671.
https://doi.org/10.1155/2016/6517313

[5]   Reddy, J.K. and Rao, M.S. (2006) Lipid Metabolism and Liver Inflammation. II. Fatty Liver Disease and Fatty Acid Oxidation. Gastrointestinal and Liver Physiology, 290, 852-858.

[6]   Fruchart, J.C. (2009) Peroxisome Proliferator-Activated Receptor-Alpha (PPARalpha): At the Crossroads of Obesity, Diabetes and Cardiovascular Disease. Atherosclerosis, 205, 1-8.
https://doi.org/10.1016/j.atherosclerosis.2009.03.008

[7]   Kersten, S. and Wahli, W. (2000) Peroxisome Proliferator Activated Receptor Agonists. EXS, 89, 141-151.

[8]   Desvergne, B. and Wahli, W. (1999) Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism. Endocrine Reviews, 20, 649-688.
https://doi.org/10.1210/er.20.5.649

[9]   Luo, W., Guo, Z., Wu, M., Hao, C., Hu, X., Zhou, Z., et al. (2013) Association of Peroxisome Proliferator-Activated Receptor Alpha/Delta/Gamma with Obesity and Gene-Gene Interaction in the Chinese Han population. Journal of Epidemiology, 23, 187-194.

[10]   Gu, S.J., Liu, M.M., Guo, Z.R., Wu, M., Chen, Q., Zhou, Z.Y., et al. (2013) Gene-Gene Interactions among Paralpha/Delta/Gamma Polymorphisms for Hypertriglyceridemia in Chinese Han population. Gene, 515, 272-176.
https://doi.org/10.1016/j.gene.2012.11.078

[11]   Gu, S.J., Guo, Z.R., Zhou, Z.Y., Hu, X.S. and Wu, M. (2014) PPAR Alpha and PPAR Gamma Polymorphisms as Risk Factors for Dyslipidemia in a Chinese Han population. Lipids in Health and Disease, 13, 23.

[12]   Zheru, D., Peiliang, F., Yuli, W., Haishan, W., Qirong, Q., Xiaohua, L., et al. (2014) Association of PPARgamma Gene Polymorphisms with Osteoarthritis in a Southeast Chinese population. Journal of Genetics, 93, 719-723.
https://doi.org/10.1007/s12041-014-0444-2

[13]   Marangoni, R.G., Korman, B.D., Allanore, Y., Dieude, P., Armstrong, L.L., Rzhetskaya, M., et al. (2015) A Candidate Gene Study Reveals Association between a Variant of the Peroxisome Proliferator-Activated Receptor Gamma (PPAR-Gamma) Gene and Systemic Sclerosis. Arthritis Research & Therapy, 17, 128.
https://doi.org/10.1186/s13075-015-0641-2

[14]   Huang, Y., Nie, S., Zhou, S., Li, K., Sun, J., Zhao, J., et al. (2015) PPARD rs2016520 Polymorphism and Circulating Lipid Levels Connect with Brain Diseases in Han Chinese and Suggest Sex-Dependent Effects. Biomedicine & Pharmacotherapy, 70, 7-11.

[15]   Lapice, E., Monticelli, A., Cocozza, S., Pinelli, M., Cocozza, S., Bruzzese, D., et al. (2015) The PPARgamma2 Pro12Ala Variant Is Protective against Progression of Nephropathy in People with Type 2 Diabetes. Journal of Translational Medicine, 13, 85.
https://doi.org/10.1186/s12967-015-0448-6

[16]   Fan, W., Shen, C., Wu, M., Zhou, Z.Y. and Guo, Z.R. (2015) Association and Interaction of PPARalpha, Delta, and Gamma Gene Polymorphisms with Low-Density Lipoprotein-Cholesterol in a Chinese Han population. Genetic Testing and Molecular Biomarkers, 19, 379-386.

[17]   Luo, W., Chen, F., Guo, Z., Wu, M., Zhou, Z. and Yao, X. (2016) A Population Association Study of PPAR Delta Gene Rs2016520 and Rs9794 Polymorphisms and Haplotypes with Body Mass Index and Waist Circumference in a Chinese Population. Annals of Human Biology, 43, 67-72.

[18]   Knight, J.C. (2003) Functional Implications of Genetic Variation in Non-Coding DNA for Disease Susceptibility and Gene Regulation. Clinical Science, 104, 493-501.
https://doi.org/10.1042/CS20020304

[19]   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.

[20]   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.
https://doi.org/10.1016/j.mrrev.2008.05.001

[21]   Buroker, N.E. (2016) Identifying Changes in Punitive Transcriptional Factor Binding Sites from Regulatory Single Nucleotide Polymoprhisms that Are Significantly Associated with Disease or Sickness. World Journal of Hematology, 5, 75-87.

[22]   Bryne, J.C., Valen, E., Tang, M.H., Marstrand, T., Winther, O., Da Piedade, I., et al. (2008) JASPAR, the Open Access Database of Transcription Factor-Binding Profiles: New Content and Tools in the 2008 Update. Nucleic Acids Research, 36, 102-106. https://doi.org/10.1093/nar/gkm955

[23]   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, 91-94.

[24]   Sandelin, A., Wasserman, W.W. and Lenhard, B. (2004) ConSite: Web-Based Prediction of Regulatory Elements Using Cross-Species Comparison. Nucleic Acids Research, 32, 249-252.
https://doi.org/10.1093/nar/gkh372

[25]   Buroker, N.E. (2013) AKT3 rSNPs, Transcritional Factor Binding Sites and Human Disease. Open Journal of Blood Diseases, 3, 116-129.
https://doi.org/10.4236/ojbd.2013.34023

[26]   Buroker, N.E. (2013) ATF3 rSNPs, Transcriptional Factor Binding Sites and Human Etiology. Open Journal of Genetics, 3, 253-261.

[27]   Buroker, N.E. (2014) ADRBK1 (GRK2) rSNPs, Transcriptional Factor Binding Sites and Cardiovascular Disease in the Black Population. Journal of Cardiovascular Disease, 2.

[28]   Buroker, N.E. (2014) DIO2 rSNPs, Transcription Factor Binding Sites and Disease. British Journal of Medicine & Medical Research, 9, 1-24.
https://doi.org/10.9734/BJMMR/2015/18535

[29]   Buroker, N.E. (2016) Computational EPAS1 rSNP Analysis, Transcriptional Factor Binding Sites and High Altitude Sickness or Adaptation. Journal of Proteomics and Genomics Research, 1, 31-59.

[30]   Buroker, N.E. (2015) LIPA rSNPs (Rs1412444 and Rs2246833), Transcriptional Factor Binding Sites and Disease. British Biomedical Bulletin, 3, 281-294.

[31]   Buroker, N.E. (2016) Computational STAT4 rSNP Analysis, Transcriptional Factor Binding Sites and Disease. Bioinformatics and Diabetes, 1, 1-36.

[32]   Buroker, N.E. (2015) VEGFA rSNPs, Transcriptional Factor Binding Sites and Human Disease. The Journal of Physiological Sciences, 64, 73-76.
https://doi.org/10.1007/s12576-013-0293-4

[33]   Buroker, N.E. (2015) VEGFA SNPs (Rs34357231 & Rs35569394), Transcriptional Factor Binding Sites and Human Disease. British Journal of Medicine & Medical Research, 10, 1-11.

[34]   Buroker, N E., Ning, X.H., Li, K., Zhou, Z.N., Cen, W.J., Wu, X.F., Zhu, W.Z., Scott, C.R. and Chen, S.H. (2015) SNPs, Linkage Disequilibrium and Transcriptional Factor Binding Sites Associated with Acute Mountain Sickness among Han Chinese at the Qinghai-Tibetan Plateau. International Journal of Genomic Medicine, 3.

[35]   Buroker, N.E., Ning, X.H., Zhou, Z.N., Li, K., Cen, W.J., Wu, X.F., et al. (2013) VEGFA SNPs and Transcriptional Factor Binding Sites Associated with High Altitude Sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau. Journal of Physiological Sciences, 63, 183-193.
https://doi.org/10.1007/s12576-013-0257-8

[36]   Buroker, N.E. (2014) SNP (rs1570360) in Transcriptional Factor Binding Sites of the VEGFA Promoter Is Associated with Hypertensive Nephropathy and Diabetic Retinopathy. Austin Journal of Endocrinology and Diabetes, 2, 5.

[37]   Shah, A., Rader, D.J. and Millar, J.S. (2010) The Effect of PPAR-Alpha Agonism on Apolipoprotein Metabolism in Humans. Atherosclerosis, 210, 35-40.

[38]   Lacquemant, C., Lepretre, F., Pineda Torra, I., Manraj, M., Charpentier, G., Ruiz, J., et al. (2000) Mutation Screening of the PPARalpha Gene in Type 2 Diabetes Associated with Coronary Heart Disease. Diabetes & Metabolism, 26, 393-401.

[39]   Vohl, M.C., Lepage, P., Gaudet, D., Brewer, C.G., Betard, C., Perron, P., et al. (2000) Molecular Scanning of the Human PPARa Gene: Association of the L162v Mutation with Hyperapobetalipoproteinemia. The Journal of Lipid Research, 41, 945-52.

[40]   Austin, E.D., Loyd, J.E. and Phillips, J.A. (1993) Heritable Pulmonary Arterial Hypertension. In: Pagon, R.A., Adam, M.P., Ardinger, H.H., Wallace, S.E., Amemiya, A., Bean, L.J.H., et al., Eds., Gene Reviews, Seattle.

[41]   Robinson, E. and Grieve, D.J. (2009) Significance of Peroxisome Proliferator-Activated Receptors in the Cardiovascular System in Health and Disease. Pharmacology & Therapeutics, 122, 246-263.
https://doi.org/10.1016/j.pharmthera.2009.03.003

[42]   Semple, R.K., Chatterjee, V.K. and O'Rahilly, S. (2006) PPAR Gamma and Human Metabolic Disease. The Journal of Clinical Investigation, 116, 581-589.

[43]   Wagh, K., Bhatia, A., Alexe, G., Reddy, A., Ravikumar, V., Seiler, M., et al. (2012) Lactase Persistence and Lipid Pathway Selection in the Maasai. PLOS ONE, 7, e44751.
https://doi.org/10.1371/journal.pone.0044751

[44]   Bahreini, A., Levine, K., Santana-Santos, L., Benos, P.V., Wang, P., Andersen, C., et al. (2016) Non-Coding Single Nucleotide Variants Affecting Estrogen Receptor Binding and Activity. Genome Medicine, 8, 128.

[45]   Flavell, D.M., Pineda Torra, I., Jamshidi, Y., Evans, D., Diamond, J.R., Elkeles, R.S., et al. (2000) Variation in the PPARalpha Gene Is Associated with Altered Function In Vitro and Plasma Lipid Concentrations in Type II Diabetic Subjects. Diabetologia, 43, 673-680.
https://doi.org/10.1007/s001250051357

[46]   Shin, M.J., Kanaya, A.M. and Krauss, R.M. (2008) Polymorphisms in the Peroxisome Proliferator Activated Receptor Alpha Gene Are Associated with Levels of Apolipoprotein CIII and Triglyceride in African-Americans but Not Caucasians. Atherosclerosis, 198, 313-319.

[47]   Wang, D., Fu, L., Ning, W., Guo, L., Sun, X., Dey, S.K., et al. (2014) Peroxisome Proliferator-Activated Receptor Delta Promotes Colonic Inflammation and Tumor Growth. Proceedings of the National Academy of Sciences, 111, 7084-7089.
https://doi.org/10.1073/pnas.1324233111

[48]   Aberle, J., Hopfer, I., Beil, F.U. and Seedorf, U. (2006) Association of the T+294C Polymorphism in PPAR Delta with Low HDL Cholesterol and Coronary Heart Disease Risk in women. International Journal of Medical Sciences, 3, 108-111.

[49]   Choi, S.W., Jeong, D.U., Kim, J.A., Lee, B., Joeng, K.S., Long, F., et al. (2012) Indian Hedgehog Signalling Triggers Nkx3.2 Protein Degradation during Chondrocyte Maturation. Biochemical Journal, 443, 789-798.
https://doi.org/10.1042/BJ20112062

[50]   Blagojevic, M., Jinks, C., Jeffery, A. and Jordan, K.P. (2010) Risk Factors for Onset of Osteoarthritis of the Knee in Older Adults: A Systematic Review and Meta-Analysis. Osteoarthritis Cartilage, 18, 24-33.

[51]   Lievense, A.M., Bierma-Zeinstra, S.M., Verhagen, A.P., Van Baar, M.E., Verhaar, J.A. and Koes, B.W. (2002) Influence of Obesity on the Development of Osteoarthritis of the Hip: A Systematic Review. Rheumatology, 41, 1155-1162.
https://doi.org/10.1093/rheumatology/41.10.1155

[52]   Adzhubei, I.A., Schmidt, S., Peshkin, L., Ramensky, V.E., Gerasimova, A., Bork, P., et al. (2010) A Method and Server for Predicting Damaging Missense Mutations. Nat Methods, 7, 248-249.
https://doi.org/10.1038/nmeth0410-248

 
 
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