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Polymorphism in the 3′-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses

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Abstract

Schizophrenia (SCZ) is a multifactorial disorder caused by environmental and genetic factors. Studies have shown that various single-nucleotide polymorphisms (SNPs) in the binding sites of microRNAs contribute to the risk of developing SCZ. We aimed to investigate whether the variants located in the 3′-UTR region of LIF (rs929271T>G) and ATF6B (rs8283G>A) were associated with increased susceptibility to SCZ in a population from the south-east of Iran. In this case-control study, a total of 396 subjects were recruited. SNPs were genotyped via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotyping results showed that the G allele of rs929271 significantly increased the risk of SCZ (OR = 1.58 95%CI = 1.19–2.10, p = 0.001). As for rs929271, the GG genotype of co-dominant (OR = 2.54 95%CI = 1.39–4.64, p = 0.002) and recessive (OR = 2.91 95%CI = 1.77–4.80, p < 0.001) models were strongly linked to SCZ. No significant differences were observed between rs8283 polymorphism and predisposition to SCZ. In silico analyses predicted that rs929271 might alter the binding sites of microRNAs, which was believed to have an unclear role in the development of SCZ. Moreover, rs929271 polymorphism changed the LIF-mRNA folding structure. These findings provide fine pieces of evidence regarding the possible effects of LIF polymorphism in the development of SCZ and regulation of the LIF gene targeted by microRNAs.

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References

  • Anandaram H (2018) A computational approach to identify microRNA (miRNA) based biomarker of Pharmacovariant from the regulation of disease pathology. MOJ Proteomics Bioinform 7:152–170

    Article  Google Scholar 

  • Barcellos LF et al (2009) High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS Genet 5:e1000696

    Article  Google Scholar 

  • Bhattacharya A, Ziebarth JD, Cui Y (2013) PolymiRTS database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways. Nucleic Acids Res 42:D86–D91

    Article  Google Scholar 

  • Black DW, Grant JE (2014) DSM-5® guidebook: the essential companion to the diagnostic and statistical manual of mental disorders. American Psychiatric Pub

  • Bruno AE, Li L, Kalabus JL, Pan Y, Yu A, Hu Z (2012) miRdSNP: a database of disease-associated SNPs and microRNA target sites on 3′UTRs of human genes. BMC Genomics 13:44

    Article  CAS  Google Scholar 

  • Cai L et al (2018) Implications of newly identified brain eQTL genes and their interactors in schizophrenia. Mol Ther Nucleic Acids 12:433–442

    Article  CAS  Google Scholar 

  • Consortium GP (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491:56

    Article  Google Scholar 

  • Ding Y, Chan CY, Lawrence CE (2004) S fold web server for statistical folding and rational design of nucleic acids. Nucleic Acids Res 32:W135–W141

    Article  CAS  Google Scholar 

  • Dolatkhah R, Somi MH, Asvadi Kermani I, Bonyadi M, Sepehri B, Boostani K, Azadbakht S, Fotouhi N, Farassati F, Dastgiri S (2016) Association between proto-oncogene mutations and clinicopathologic characteristics and overall survival in colorectal cancer in East Azerbaijan. Iran OncolTargets Ther 9:7385–7395

    Article  Google Scholar 

  • Ekimler S, Sahin K (2014) Computational methods for microRNA target prediction. Genes 5:671–683

    Article  Google Scholar 

  • Gill M et al (1996) A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Am J Med Genet 67:40–45

    Article  CAS  Google Scholar 

  • Gong Y, Wu CN, Xu J, Feng G, Xing QH, Fu W, Li C, He L, Zhao XZ (2013) Polymorphisms in microRNA target sites influence susceptibility to schizophrenia by altering the binding of miRNAs to their targets. Eur Neuropsychopharmacol 23:1182–1189

    Article  CAS  Google Scholar 

  • Green MF, Kern RS, Heaton RK (2004) Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 72:41–51

    Article  Google Scholar 

  • Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ (2011) Biological functions of microRNAs: a review. J Physiol Biochem 67:129–139

    Article  CAS  Google Scholar 

  • Im H-I, Kenny PJ (2012) MicroRNAs in neuronal function and dysfunction. Trends Neurosci 35:325–334

    Article  CAS  Google Scholar 

  • Jiang J, Long J, Ling W, Huang G, Su L (2017) Genetic variation in the 3′-untranslated region of PAK1 influences schizophrenia susceptibility. Exp Ther Med 13:1101–1108

    Article  CAS  Google Scholar 

  • Kang H-J et al (2009) Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci 106:9761–9766

    Article  CAS  Google Scholar 

  • Lan X, Chen Q, Wang Y, Jia B, Sun L, Zheng J, Peng H (2012) TNF-α affects human cortical neural progenitor cell differentiation through the autocrine secretion of leukemia inhibitory factor. PLoS One 7(12)

  • Liu J, Yu H, Hu W (2015) LIF is a new p53 negative regulator. J Nat Sci 1:e131

    PubMed  PubMed Central  Google Scholar 

  • Loohuis NO, Kos A, Martens G, Van Bokhoven H, Kasri NN, Aschrafi A (2012) MicroRNA networks direct neuronal development and plasticity. Cell Mol Life Sci 69:89–102

    Article  Google Scholar 

  • Madden T (2013) The BLAST sequence analysis tool. In: The NCBI Handbook [Internet], 2nd edn. National Center for Biotechnology Information (US)

  • Meyer U, Feldon J, Yee BK (2008) A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr Bull 35:959–972

    Article  Google Scholar 

  • Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  CAS  Google Scholar 

  • Mokhtari R, Lachman HM (2016) The major histocompatibility complex (MHC) in schizophrenia: a review. J Clin Cell Immunol 7(6):479

  • Moszyńska A, Gebert M, Collawn JF, Bartoszewski R (2017) SNPs in microRNA target sites and their potential role in human disease. Open Biol 7:170019

    Article  Google Scholar 

  • Nakanishi M, Niidome T, Matsuda S, Akaike A, Kihara T, Sugimoto H (2007) Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur J Neurosci 25:649–658

    Article  Google Scholar 

  • Nicola NA, Babon JJ (2015) Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev 26:533–544

    Article  CAS  Google Scholar 

  • Noto C, Maes M, Ota VK, Teixeira AL, Bressan RA, Gadelha A, Brietzke E (2015) High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World J Biol Psychiatry 16:422–429

    Article  Google Scholar 

  • O'donovan MC et al (2008) Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 40:1053

    Article  CAS  Google Scholar 

  • Okahisa Y et al (2010) Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. Prog Neuro-Psychopharmacol Biol Psychiatry 34:172–176

    Article  CAS  Google Scholar 

  • Oliveira JBA et al (2016) Association between leukaemia inhibitory factor gene polymorphism and pregnancy outcomes after assisted reproduction techniques. Reprod BioMed Online 32:66–78

    Article  CAS  Google Scholar 

  • Park T-J et al (2014) Polymorphisms of ATF6B are potentially associated with fev1 decline by aspirin provocation in asthmatics. Allergy, Asthma Immunol Res 6:142–148

    Article  CAS  Google Scholar 

  • Sabarinathan R, Tafer H, Seemann SE, Hofacker IL, Stadler PF, Gorodkin J (2013) The RNAsnp web server: predicting SNP effects on local RNA secondary structure. Nucleic Acids Res 41:W475–W479

    Article  Google Scholar 

  • Sargazi S, Nia MH, Saravani R, Shahroudi MJ, Jahantigh D, Shakiba M (2020) IGF2BP2 polymorphisms as genetic biomarkers for either schizophrenia or type 2 diabetes mellitus: a case-control study. Gene Rep:100680

  • Shanware NP, Zhan L, Hutchinson JA, Kim SH, Williams LM, Tibbetts RS (2010) Conserved and distinct modes of CREB/ATF transcription factor regulation by PP2A/B56γ and genotoxic stress. PLoS One 5:e12173

    Article  Google Scholar 

  • Steffek AE, McCullumsmith RE, Haroutunian V, Meador-Woodruff JH (2008) Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia. Schizophr Res 103:71–82

    Article  Google Scholar 

  • Wei J, Hemmings G (2004) TNXB locus may be a candidate gene predisposing to schizophrenia. Am J Med Genet B Neuropsychiatr Genet 125:43–49

    Article  Google Scholar 

  • Williams HJ, Owen MJ, O'Donovan MC (2009) Schizophrenia genetics: new insights from new approaches. Br Med Bull 91(1):61–74

  • Wray NR, Goddard ME (2010) Multi-locus models of genetic risk of disease. Genome Med 2:10

    Article  Google Scholar 

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Acknowledgments

The authors wish to thank the technical operators of the psychiatric clinic of Baharan Hospital (Zahedan, Iran).

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Authors and Affiliations

  1. Genetics of Non-Communicable Disease Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran

    Mahdiyeh Moudi

  2. Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran

    Saman Sargazi, Milad Heidari Nia & Ramin Saravani

  3. Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

    Ramin Saravani

  4. Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Milad Shirvaliloo

  5. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Milad Shirvaliloo

  6. Department of Psychiatry, Zahedan University of Medical Sciences, Zahedan, Iran

    Mansoor Shakiba

  7. Psychosomatic Research Center, Imam Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Mansoor Shakiba

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  1. Mahdiyeh Moudi
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  2. Saman Sargazi
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  3. Milad Heidari Nia
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  4. Ramin Saravani
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  5. Milad Shirvaliloo
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Correspondence to Saman Sargazi or Ramin Saravani.

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Moudi, M., Sargazi, S., Heidari Nia, M. et al. Polymorphism in the 3′-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses. J Mol Neurosci 70, 2093–2101 (2020). https://doi.org/10.1007/s12031-020-01616-6

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  • DOI: https://doi.org/10.1007/s12031-020-01616-6

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