The C161T Polymorphism in Peroxisome Proliferator-Activated Receptor ɣ2, but Not Pro12Ala, Is Associated with Diabetic Retinopathy in Type 2 Diabetes Mellitus in an Egyptian Population


Objectives: Diabetic retinopathy (DR) is one of the most common microvascular complications of type 2 diabetes mellitus (T2DM). It is multifactorial with the contribution of multiple genetic factors. We questioned the association of polymorphisms in the peroxisome proliferator-activated receptor ?2 (PPAR?2) gene (Pro12Ala and C161T) with DR in an Egyptian population. Methods: This case control study included one hundred healthy individuals and 252 T2DM among them 122 with DR and 130 without DR. Genotyping was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Results: The Pro12Ala Ala allele was associated with decreased risk of DR with an odds ratio (OR) of 0.484, 95% confidence interval (CI) (0.254 - 0.920), and a p value = 0.024. The C161T T allele was associated with increased risk of DR with OR = 2.593, 95% CI (1.672 - 4.020), p < 0.001. However, when considering other covariates such as glycosylated hemoglobin (HbA1c) in multivariate regression analysis only C161T was associated with increased risk of DR with OR = 3.479, 95% CI (1.907 - 6.346), p < 0.001, while the significant association with Pro12Ala was lost. HbA1c was higher in Pro/Pro genotype when compared to those with Ala/Ala and Pro/Ala genotypes. Conclusion: We report that T allele of C161T increased risk of DR in the studied population. Further studies are warranted to investigate functional implications of polymorphisms of the PPAR-? gene in DR development.

Share and Cite:

Ramadan, R. , Zaki, M. , Sharkawy, R. , Desouky, L. , Madkour, M. and Kamel, K. (2016) The C161T Polymorphism in Peroxisome Proliferator-Activated Receptor ɣ2, but Not Pro12Ala, Is Associated with Diabetic Retinopathy in Type 2 Diabetes Mellitus in an Egyptian Population. Journal of Diabetes Mellitus, 6, 1-9. doi: 10.4236/jdm.2016.61001.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] American Diabetes Association (2014) Standards of Medical Care in Diabetes-2014. Diabetes Care, 37, S14-S80.
[2] Ma, J., Li, Y., Zhou, F., Xu, X., Guo, G. and Qu, Y. (2012) Meta-Analysis of Association between the Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor-γ2 Gene and Diabetic Retinopathy in Caucasians and Asians. Molecular Vision, 18, 2352-2360.
[3] Granier, C., Makni, K., Molina, L., Jardin-Watelet, B., Ayadi, H. and Jarraya, F. (2008) Gene and Protein Markers of Diabetic Nephropathy. Nephrology Dialysis Transplantation, 23,792-799.
[4] Sheu, W.H., Kuo, J.Z., Lee, I.T., Hung, Y.-J., Lee, W.-J., Tsai, H.-Y., et al. (2013) Genome-Wide Association Study in a Chinese Population with Diabetic Retinopathy. Human Molecular Genetics, 22, 3165-3173.
[5] Youssef, S.M., Mohamed, N., Afef, S., Khaldoun, B.H., Fadoua, N., Fadhel, N.M., et al. (2014) Combined Effects of the C161T and Pro12Ala PPARγ2 Gene Variants with Insulin Resistance on Metabolic Syndrome: A Case-Control Study of a Central Tunisian Population. Journal of Molecular Neuroscience, 52, 487-492.
[6] Gouda, H.N., Sagoo, G.S., Harding, A.H., Yates, J., Sandhu, M.S. and Higgins, J.P.T. (2010) The Association between the Peroxisome Proliferator-Activated Receptor-γ2 (PPARG2) Pro12Ala Gene Variant and Type 2 Diabetes Mellitus: A HuGE Review and Meta-Analysis. American Journal of Epidemiology, 171, 645-655.
[7] Grarup, N., Sandholt, C.H., Hansen, T. and Pedersen, O. (2014) Genetic Susceptibility to Type 2 Diabetes and Obesity: From Genome-Wide Association Studies to Rare Variants and Beyond. Diabetologia, 57, 1528-1541.
[8] Liu, Y., Yuan, Z., Liu, Y., Zhang, J.J., Yin, P., Wang, D.Q., et al. (2007) PPAR Gamma Gene C161T Substitution Is Associated with Reduced Risk of Coronary Artery Disease and Decreased Proinflammatory Cytokine Expression. American Heart Journal, 154,718-724.
[9] Tawfik, A., Sanders, T., Kahook, K., Akeel, S., Elmarakby, A. and Al-Shabrawey, M. (2009) Suppression of Retinal Peroxisome Proliferator-Activated Receptor Gamma in Experimental Diabetes and Oxygen-Induced Retinopathy: Role of NADPH Oxidase. Investigative Ophthalmology and Visual Science, 50, 878-884.
[10] Muranaka, K., Yanagi, Y., Tamaki, Y., Usui, T., Kubota, N., Iriyama, A., et al. (2006) Effects of Peroxisome Proliferator-Activated Receptor γ and Its Ligand on Blood Retinal Barrier in a Streptozotocin-Induced Diabetic Model. Investigative Ophthalmology and Visual Science, 47, 4547-4552.
[11] Petrovic, M.G., Kunej, T., Peterlin, B., Dovc, P. and Petrovic, D. (2005) Gly482Ser Polymorphism of the Peroxisome Proliferator Activated Receptor-γ Coactivator-1 Gene Might Be a Risk Factor for Diabetic Retinopathy in Slovene Population (Caucasians) with Type 2 Diabetes and the Pro12Ala Polymorphism of the PPARγ Gene Is Not. Diabetes Metabolism Research and Reviews, 21, 470-474.
[12] Radha, V., Vimaleswaran, K.S., Babu, H.N., et al. (2006) Role of Genetic Polymorphism Peroxisome Proliferator-Activated Receptor-γ2 Pro12Ala on Ethnic Susceptibility to Diabetes in South-Asian and Caucasian Subjects: Evidence for Heterogeneity. Diabetes Care, 29, 1046-1051.
[13] Costa, V., Casamassimi, A., Esposito, K., et al. (2009) Characterization of a Novel Polymorphism in PPARG Regulatory Region Associated with Type 2 Diabetes and Diabetic Retinopathy in Italy. Journal of Biomedicine and Biotechnology, 2009, Article ID: 126917.
[14] Liu, D.X., Qi, H., Li, L.S. and Guo, J.C. (2008) Association of Peroxisome Proliferator-Activated Receptor-γ Gene Pro12Ala and C161T Polymorphisms with Metabolic Syndrome. Circulation Journal, 72, 551-557.
[15] Song, M.K., Roufogalis, B.D. and Huang, T.H. (2012) Modulation of Diabetic Retinopathy Pathophysiology by Natural Medicines through PPAR-γ-Related Pharmacology. British Journal of Pharmacology, 165, 4-19.
[16] Paracchini, V. and Taioli, E. (2005) Genetics of Leptin and Obesity: A HuGE Review. American Journal Epidemiology, 162, 101-114.
[17] Luan, J., Browne, P.O., Harding, A.H., Halsall, D.J., O’Rahilly, S., Chatterjee, V.K. and Wareham, N.J. (2001) Evidence for Gene-Nutrient Interaction at the PPAR Gamma Locus. Diabetes, 50, 686-689.
[18] Thamer, C., Haap, M., Volk, A., et al. (2002) Evidence for Greater Oxidative Substrate Flexibility in Male Carriers of the Pro 12 Ala Polymorphism in PPAR-γ2. Hormone and Metabolic Research, 34, 132-136.
[19] Luo, W., Cao, J., Li, J. and He, W. (2008) Adipose Tissue Specific PPAR Gamma Deficiency Increases Resistance to Oxidative Stress. Experimental Gerontology, 43, 154-163.
[20] Liu, L., Zheng, T., Wang, F., et al. (2010) Pro12Ala Polymorphism in the PPARG Gene Contributes to the Development of Diabetic Nephropathy in Chinese Type 2 Diabetic Patients. Diabetes Care, 33, 144-149.
[21] Malecki, M.T., Cyganek, K., Mirkiewicz-Sieradzka, B., et al. (2008) Alanine Variant of the Pro12Ala Polymorphism of the PPARγ Gene Might Be Associated with Decreased Risk of Diabetic Retinopathy in Type 2 Diabetes. Diabetes Research and Clinical Practice, 80, 139-145.
[22] Zietz, B., Barth, N., Spiegel, D., Schmitz, G., Scholmerich, J. and Schaffler, A. (2002) Pro12Ala Polymorphism in the Peroxisome Proliferator-Activated Receptor-γ2 (PPARγ2) Is Associated with Higher Levels of Total Cholesterol and LDL-Cholesterol in Male Caucasian Type 2 Diabetes Patients. Experimental and Clinical Endocrinology and Diabetes, 110, 60-66.
[23] Chehaibi, K., Nouira, S., Mahdouani, K., Hamdi, S., Rouis, M. and Slimane, M.N. (2014) Effect of the PPARγ C161T Gene Variant on Serum Lipids in Ischemic Stroke Patients with and without Type 2 Diabetes Mellitus. Journal of Molecular Neuroscience, 54, 730-738.
[24] Rooki, H., Haerian, M.S., Azimzadeh, P., et al. (2013) Distribution and Genotype Frequency of the C1431T and Pro12ala Polymorphisms of the Peroxisome Proliferator Activator Receptor Gamma Gene in an Iranian Population. Indian Journal of Human Genetics, 19, 423-429.
[25] Yang, L.L., Hua, Q., Liu, R.K. and Yang, Z. (2009) Association between Two Common Polymorphisms of PPAR Gamma Gene and Metabolic Syndrome Families in a Chinese Population. Archives of Medical Research, 40, 89-96.
[26] Wang, X.L., Oosterhof, J. and Duarte, N. (1999) Peroxisome Proliferator-Activated Receptor Gamma C161→T Polymorphism and Coronary Artery Disease. Cardiovascular Research, 44, 588-594.
[27] Blüher, M., Klemm, T., Gerike, T., Krankenberg, H., Schuler, G. and Paschke, R. (2002) Lack of Association between Peroxisome Proliferator-Activated Receptor-Gamma-2 Gene Variants and the Occurrence of Coronary Heart Disease in Patients with Diabetes Mellitus. European Journal of Endocrinology, 146, 545-551.
[28] Wan, J., Xiong, S.X., Chao, S.P., et al. (2010) PPARγ Gene C161T Substitution Alters Lipid Profile in Chinese Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus. Cardiovascular Diabetology, 9, 13.
[29] Ding, S., Liu, L., Zhuge, Q.C., Yu, Z., Zhang, X. and Xie, J. (2012) The Meta-Analysis of the Association of PPARG P12A, C161T Polymorphism and Coronary Heart Disease. Wiener klinische Wochenschrift, 124, 671-677.
[30] Siezen, C.L., van Leeuwen, A.I., Kram, N.R., Luken, M.E., van Kranen, H.J. and Kampman, E. (2005) Colorectal Adenoma Risk Is Modified by the Interplay between Polymorphisms in Arachidonic Acid Pathway Genes and Fish Consumption. Carcinogenesis, 26, 449-457.
[31] Jiang, J., Gajalakshmi, V., Wang, J., et al. (2005) Influence of the C161T but Not Pro12Ala Polymorphism in the Peroxisome Proliferator Activated Receptor Gamma on Colorectal Cancer in an Indian Population. Cancer Science, 96, 507-512.
[32] Shrestha, U.K., Karimi, O., Crusius, J.B., et al. (2009) Distribution of Peroxisome Proliferator-Activated Receptor-Gamma Polymorphisms in Chinese and Dutch Patients with Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 16, 312-319.
[33] Tamaki, J., Iki, M., Morita, A., et al. (2010) Peroxisome Proliferator-Activated Receptor Gamma Polymorphism Is Related to Peak Bone Mass: The JPOS Study. Osteoporosis International, 21, 321-329.
[34] Reiter, C.E., Wu, X., Sandirasegarane, L., et al. (2006) Diabetes Reduces Basal Retinal Insulin Receptor Signalling. Reversal with Systemic and Local Insulin. Diabetes, 55, 1148-1156.
[35] Moffett, S.P., Feingold, E., Barmada, M.M., et al. (2005) The C161→T Polymorphism in Peroxisome Proliferator-Activated Receptor Gamma, but Not P12A, Is Associated with Insulin Resistance in Hispanic and Non-Hispanic White Women: Evidence for Another Functional Variant in Peroxisome Proliferator-Activated Receptor Gamma. Metabolism, 54, 1552-1556.
[36] Tavares, V., Hirata, R.D., Rodrigues, A.C., et al. (2005) Effect of the Peroxisome Proliferator-Activated Receptor-Gamma C161T Polymorphism on Lipid Profile in Brazilian Patients with Type 2 Diabetes Mellitus. Journal of Endocrinological Investigations, 28, 129-136.
[37] Rhee, E.J., Oh, K.W., Lee, W.Y., et al. (2006) Effects of Two Common Polymorphisms of Peroxisome Proliferator-Activated Receptor-γ Gene on Metabolic Syndrome. Archives of Medical Research, 37, 86-94.
[38] Meirhaeghe, A., Fajas, L., Helbecque, N., et al. (1998) A Genetic Polymorphism of the Peroxisome Proliferator-Activated Receptor Gamma Gene Influences Plasma Leptin Levels in Obese Humans. Human Molecular Genetics, 7, 435-440.
[39] Uckaya, G., Ozata, M., Bayraktar, Z., Erten, V., Bingol, N. and Ozdemir, C. (2000) Is Leptin Associated with Diabetic Retinopathy? Diabetes Care, 23, 371-376.
[40] Suganami, E., Takagi, H., Ohashi, H., et al. (2004) Leptin Stimulates Ischemia-Induced Retinal Neovascularization. Diabetes, 53, 2443-2448.
[41] Er, H., Doganay, S., Ozerol, E. and Yurekli, M. (2005) Adrenomedullin and Leptin Levels in Diabetic Retinopathy and Retinal Diseases. Ophthalmologica, 219, 107-111.
[42] Caramori, M.L., Canani, L.H., Costa, L.A. and Gross, J.L. (2003) The Human Peroxisome Proliferator-Activated Receptor γ2 (PPARγ2) Pro12Ala Polymorphism Is Associated with Decreased Risk of Diabetic Nephropathy in Patients with Type 2 Diabetes. Diabetes, 52, 3010-3013.
[43] Shah, A., Sheth, F., Majumder, A., et al. (2014) Effect of PPAR-γ2 Gene Pro12Ala and ADR-β3 Gene Trp64AArg Polymorphism on Glucose Homeostasis in Type 2 Diabetes Subjects from Western India. Molecular Cytogenetics, 7, 101.
[44] Bener, A., Zirie, M., Aoaa, H., Nawaz, Z., Samson, N. and Mohammad, R. (2015) Impact of the Pro12Ala Polymorphism of the PPARγ2 Gene on Diabetes and Obesity in a Highly Consanguineous Population. Indian Journal of Endocrinology and Metabolism, 19, 77-83.
[45] Zhang, S., Gu, H. and Hu. N. (2015) Role of Peroxisome Proliferator-Activated Receptor γ in Ocular Diseases. Journal of Ophthalmology, 2015, Article ID: 275435.

Copyright © 2022 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.