Impact of Proliferator-Activated Receptor γ Gene Polymorphisms on Risk of Schizophrenia: A Case-Control Study and Computational Analyses
-
Saman Sargazi
,
Fariba Mirani Sargazi
,
Mahdiyeh Moudi
,
Milad Heidari Nia
,
Ramin Saravani
,
Shekoufeh Mirinejad
,
Sheida Shahraki
,
Mansoor Shakiba
Abstract
Objective: Schizophrenia (SCZ) is a common psychiatric disorder characterized by a complex mode of inheritance. Peroxisome proliferator-activated receptor-γ (PPARG) mainly regulates lipid and glucose metabolisms while it is constitutively expressed in rat primary microglial cultures. This preliminary study was aimed to investigate the relationship of two polymorphisms in the PPARG gene, rs1801282 C/G, and rs3856806 C/T, to the risk of SCZ in the southeast Iranian population.
Method: A total of 300 participants (150 patients with SCZ and 150 healthy controls) were enrolled. Genotyping was done using the amplification refractory mutation system polymerase chain reaction (ARMS–PCR) technique. Computational analyses were carried out to predict the potential effects of the studied polymorphisms.
Results: A significant link was found between genotypes of rs1801282 and SCZ susceptibility. The G allele of rs1801282 in CG and GG form of the codominant model increased the risk of SCZ by 2.49 and 2.64 folds, respectively. With regards to rs3856806, enhanced risk of SCZ was also observed under different inheritance models except for the overdominant model. Also, the T allele of rs3856806 enhanced the risk of SCZ by 3.19 fold. Computational analyses predicted that rs1801282 polymorphism might alter the secondary structure of PPARG-mRNA and protein function. At the same time, the other variant created the binding sites for some enhancer and silencer motifs.
Conclusion: Our findings showed that PPARG rs1821282 and rs3856806 polymorphisms associate with SCZ susceptibility. Replication studies in different ethnicities with a larger population are needed to validate our findings.
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26. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004;429(6993):771-6.
27. Barbieri M, Bonafè M, Rizzo MR, Ragno E, Olivieri F, Marchegiani F, et al. Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)gamma-2 with longevity. Exp Gerontol. 2004;39(7):1095-100.
28. Bouskila M, Pajvani UB, Scherer PE. Adiponectin: a relevant player in PPARgamma-agonist-mediated improvements in hepatic insulin sensitivity? Int J Obes (Lond). 2005;29 Suppl 1:S17-23.
29. Rizzo G, Fiorucci S. PPARs and other nuclear receptors in inflammation. Curr Opin Pharmacol. 2006;6(4):421-7.
30. Herken H, Erdal M, Aydin N, Sengul C, Karadag F, Barlas O, et al. The association of olanzapine-induced weight gain with peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism in patients with schizophrenia. DNA Cell Biol. 2009;28(10):515-9.
31. Ben Ali S, Ben Yahia F, Sediri Y, Kallel A, Ftouhi B, Feki M, et al. Gender-specific effect of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma-2 gene on obesity risk and leptin levels in a Tunisian population. Clin Biochem. 2009;42(16-17):1642-7.
32. Staeker J, Leucht S, Steimer W. Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala: lack of association with weight gain in psychiatric inpatients treated with olanzapine or clozapine. Mol Diagn Ther. 2012;16(2):93-8.
2. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet. 2003;73(1):34-48.
3. Tsuang MT, Stone WS, Faraone SV. Genes, environment and schizophrenia. Br J Psychiatry Suppl. 2001;40:s18-24.
4. Sargazi S, Nia MH, Saravani R, Shahroudi MJ, Jahantigh D, Shakiba M. IGF2BP2 polymorphisms as genetic biomarkers for either schizophrenia or type 2 diabetes mellitus: A case-control study. Gene Rep. 2020; 17:100680.
5. Andreasen N, Nasrallah HA, Dunn V, Olson SC, Grove WM, Ehrhardt JC, et al. Structural abnormalities in the frontal system in schizophrenia. A magnetic resonance imaging study. Arch Gen Psychiatry. 1986;43(2):136-44.
6. Roberts GW. Schizophrenia: a neuropathological perspective. Br J Psychiatry. 1991;158:8-17.
7. Tsai G, Yang P, Chung LC, Lange N, Coyle JT. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 1998;44(11):1081-9.
8. Diab A, Hussain RZ, Lovett-Racke AE, Chavis JA, Drew PD, Racke MK. Ligands for the peroxisome proliferator-activated receptor-gamma and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004;148(1-2):116-26.
9. Saremi L, Lotfipanah S, Mohammadi M, Hosseinzadeh H, Fathi-Kazerooni M, Johari B, et al. The Pro12Ala polymorphism in the PPAR-γ2 gene is not associated with an increased risk of NAFLD in Iranian patients with type 2 diabetes mellitus. Cell Mol Biol Lett. 2019;24:12.
10. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001;7(1):48-52.
11. Hinz B, Brune K, Pahl A. 15-Deoxy-Delta(12,14)-prostaglandin J2 inhibits the expression of proinflammatory genes in human blood monocytes via a PPAR-gamma-independent mechanism. Biochem Biophys Res Commun. 2003;302(2):415-20.
12. Hong C, Tontonoz P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev. 2008;18(5):461-7.
13. Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 2007;28(12):551-8.
14. Derosa G, Maffioli P. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists on glycemic control, lipid profile and cardiovascular risk. Curr Mol Pharmacol. 2012;5(2):272-81.
15. Liu YR, Hu TM, Lan TH, Chiu HJ, Chang YH, Chen SF, et al. Association of the PPAR-γ Gene with Altered Glucose Levels and Psychosis Profile in Schizophrenia Patients Exposed to Antipsychotics. Psychiatry Investig. 2014;11(2):179-85.
16. Mao Q, Guo H, Gao L, Wang H, Ma X. Peroxisome proliferator-activated receptor γ2 Pro12Ala (rs1801282) polymorphism and breast cancer susceptibility: a meta-analysis. Mol Med Rep. 2013;8(6):1773-8.
17. Consortium GP. A global reference for human genetic variation. Nature. 2015;526(7571):68-74.
18. Schwab SG, Knapp M, Mondabon S, Hallmayer J, Borrmann-Hassenbach M, Albus M, et al. Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. Am J Hum Genet. 2003;72(1):185-90.
19. Black DW, Grant JE. DSM-5® guidebook: the essential companion to the diagnostic and statistical manual of mental disorders: American Psychiatric Pub; 2014.
20. Puzyrev VP, Freidin MB. Genetic view on the phenomenon of combined diseases in man. Acta Naturae. 2009;1(3):52-7.
21. Bromberg Y, Rost B. SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res. 2007;35(11):3823-35.
22. Chen H, Gu F, Huang Z. Improved Chou-Fasman method for protein secondary structure prediction. BMC Bioinformatics. 2006;7 Suppl 4(Suppl 4):S14.
23. Piva F, Giulietti M, Burini AB, Principato G. SpliceAid 2: a database of human splicing factors expression data and RNA target motifs. Hum Mutat. 2012;33(1):81-5.
24. Crooks GE, Hon G, Chandonia JM, Brenner SE. WebLogo: a sequence logo generator. Genome Res. 2004;14(6):1188-90.
25. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV, et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet. 2002;71(2):337-48.
26. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004;429(6993):771-6.
27. Barbieri M, Bonafè M, Rizzo MR, Ragno E, Olivieri F, Marchegiani F, et al. Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)gamma-2 with longevity. Exp Gerontol. 2004;39(7):1095-100.
28. Bouskila M, Pajvani UB, Scherer PE. Adiponectin: a relevant player in PPARgamma-agonist-mediated improvements in hepatic insulin sensitivity? Int J Obes (Lond). 2005;29 Suppl 1:S17-23.
29. Rizzo G, Fiorucci S. PPARs and other nuclear receptors in inflammation. Curr Opin Pharmacol. 2006;6(4):421-7.
30. Herken H, Erdal M, Aydin N, Sengul C, Karadag F, Barlas O, et al. The association of olanzapine-induced weight gain with peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism in patients with schizophrenia. DNA Cell Biol. 2009;28(10):515-9.
31. Ben Ali S, Ben Yahia F, Sediri Y, Kallel A, Ftouhi B, Feki M, et al. Gender-specific effect of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma-2 gene on obesity risk and leptin levels in a Tunisian population. Clin Biochem. 2009;42(16-17):1642-7.
32. Staeker J, Leucht S, Steimer W. Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala: lack of association with weight gain in psychiatric inpatients treated with olanzapine or clozapine. Mol Diagn Ther. 2012;16(2):93-8.
| Files | ||
| Issue | Vol 15 No 4 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijps.v15i4.4294 | |
| PMCID | PMC7610076 | |
| PMID | 33240378 | |
| Keywords | ||
| Peroxisome Proliferator-Activated Receptor-γ (PPAR Gamma) Polymorphism rs1801282 rs3856806 Schizophrenia | ||
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How to Cite
1.
Sargazi S, Mirani Sargazi F, Moudi M, Heidari Nia M, Saravani R, Mirinejad S, Shahraki S, Shakiba M. Impact of Proliferator-Activated Receptor γ Gene Polymorphisms on Risk of Schizophrenia: A Case-Control Study and Computational Analyses. Iran J Psychiatry. 2020;15(4):286-296.
