Involvement of CXCL10 Rs4256246, CXCR4 Rs2228014, CCR2 Rs1799864 and CXCL16 Rs2277680 in the Predisposition to Schizophrenia

Overview

Journal J Mol Neurosci

Specialties Molecular Biology
Neurology

Date 2024 Sep 12

PMID 39264476

Authors

Hana Saoud

Hajer Foddha

Youssef Aflouk

Besma Bel Hadj Jrad

Affiliations

Soon will be listed here.

Abstract

Chemokine ligands and their receptors have acquired less attention than pro- and anti-inflammatory cytokines in schizophrenia (SCZ). Thus, we aimed to examine the impact of functional polymorphisms of the chemokine genes CXCL10, CXCL16, CXCR4, and CCR2 in the development of SCZ. Using PCR-RFLP, we analyzed the selected polymorphisms in a Tunisian cohort composed of 200 patients with SCZ and 200 healthy controls. Our preliminary data suggest that the minor allele A of CXCL10 rs4256246 is significantly associated with likelihood of SCZ (P = 0.00002) and more precisely to paranoid patients with late-onset SCZ (P = 0.0007). However, the mutated allele T of CXCR4 rs2228014 showed a significant protective impact against SCZ (P = 0.000007) and especially to male sex (P = 0.000003). This effect persists among the undifferentiated patients with early-onset SCZ (P = 0.002). Following the stratified analyses, CCR2 rs1799864 and CXCL16 rs2277680 were significantly correlated with the clinical symptoms among disorganized patients. As regards haplotype analysis, we noted that GATG haplotype was associated with protection against SCZ (P = 0.0087) but the AGCG haplotype was correlated with susceptibility to this disease (P = 0.014). Our preliminary results suggested that CXCL10 rs4256246 enhanced susceptibility to SCZ, while CXCR4 rs2228014 seemed to be protective factor. Furthermore, we identified a substantial correlation between CCR2 rs1799864 and CXCL16 rs2277680 with the clinical signs of the disorder. To validate these results and clarify the functional significance of the targeted polymorphisms in SCZ, more independent research is needed.

References

Alimoradi N, Tahami M, Firouzabadi N, Haem E, Ramezani A . Metformin attenuates symptoms of osteoarthritis: role of genetic diversity of Bcl2 and CXCL16 in OA. Arthritis Res Ther. 2023; 25(1):35. PMC: 9990216. DOI: 10.1186/s13075-023-03025-7. View

Anttila S, Kampman O, Illi A, Roivas M, Mattila K, Lassila V . NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia. Psychiatr Genet. 2003; 13(2):61-4. DOI: 10.1097/01.ypg.0000056681.82896.6b. View

Asevedo E, Gadelha A, Noto C, Mansur R, Zugman A, Belangero S . Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia. J Psychiatr Res. 2013; 47(10):1376-82. DOI: 10.1016/j.jpsychires.2013.05.032. View

Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G . Chemokines and their receptors in the central nervous system. Front Neuroendocrinol. 2001; 22(3):147-84. DOI: 10.1006/frne.2001.0214. View

Afia A, Aflouk Y, Saoud H, Zaafrane F, Gaha L, Jrad B . Inteurleukin-8 gene variations and the susceptibility to schizophrenia. Psychiatry Res. 2020; 293:113421. DOI: 10.1016/j.psychres.2020.113421. View

Bradburn S, McPhee J, Bagley L, Carroll M, Slevin M, Al-Shanti N . Dysregulation of C-X-C motif ligand 10 during aging and association with cognitive performance. Neurobiol Aging. 2017; 63:54-64. PMC: 5805841. DOI: 10.1016/j.neurobiolaging.2017.11.009. View

Cao Y, Wang F, Wang Y, Long J . Agomelatine prevents macrophage infiltration and brain endothelial cell damage in a stroke mouse model. Aging (Albany NY). 2021; 13(10):13548-13559. PMC: 8202857. DOI: 10.18632/aging.202836. View

Cho J, Nelson T, Bajova H, Gruol D . Chronic CXCL10 alters neuronal properties in rat hippocampal culture. J Neuroimmunol. 2009; 207(1-2):92-100. PMC: 2817940. DOI: 10.1016/j.jneuroim.2008.12.007. View

Dasdemir S, Kucukali C, Bireller E, Tuzun E, Cakmakoglu B . Chemokine gene variants in schizophrenia. Nord J Psychiatry. 2016; 70(6):407-12. DOI: 10.3109/08039488.2016.1141981. View

10.

de Campos-Carli S, Araujo M, de Oliveira Silveira A, Bortolo de Rezende V, Rocha N, Ferretjans R . Cannabinoid receptors on peripheral leukocytes from patients with schizophrenia: Evidence for defective immunomodulatory mechanisms. J Psychiatr Res. 2016; 87:44-52. DOI: 10.1016/j.jpsychires.2016.12.001. View

11.

Douki S, Nacef F, Benzineb S, Ben Amor C . [Schizophrenia and culture: reality and perspectives based on the Tunisian experience]. Encephale. 2007; 33(1):21-9. DOI: 10.1016/s0013-7006(07)91555-9. View

12.

Du Y, Yu Y, Hu Y, Li X, Wei Z, Pan R . Genome-Wide, Integrative Analysis Implicates Exosome-Derived MicroRNA Dysregulation in Schizophrenia. Schizophr Bull. 2019; 45(6):1257-1266. PMC: 6811837. DOI: 10.1093/schbul/sby191. View

13.

Du Y, Li X, Chen L, Chen G, Cheng Y . A Network Analysis of Epigenetic and Transcriptional Regulation in a Neurodevelopmental Rat Model of Schizophrenia With Implications for Translational Research. Schizophr Bull. 2019; 46(3):612-622. PMC: 7147587. DOI: 10.1093/schbul/sbz114. View

14.

Firasat S, Raza A, Abid A, Aziz T, Mubarak M, Anwar Naqvi S . The effect of chemokine receptor gene polymorphisms (CCR2V64I, CCR5-59029G>A and CCR5Δ32) on renal allograft survival in Pakistani transplant patients. Gene. 2012; 511(2):314-9. DOI: 10.1016/j.gene.2012.09.099. View

15.

Frankle W, Lerma J, Laruelle M . The synaptic hypothesis of schizophrenia. Neuron. 2003; 39(2):205-16. DOI: 10.1016/s0896-6273(03)00423-9. View

16.

Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E . Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol. 2006; 63(4):538-43. DOI: 10.1001/archneur.63.4.538. View

17.

Gozzi A, Large C, Schwarz A, Bertani S, Crestan V, Bifone A . Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. Neuropsychopharmacology. 2007; 33(7):1690-703. DOI: 10.1038/sj.npp.1301547. View

18.

Harrison P, Tunbridge E . Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology. 2007; 33(13):3037-45. DOI: 10.1038/sj.npp.1301543. View

19.

Hong S, Lee E, Martin A, Soontornniyomkij B, Soontornniyomkij V, Achim C . Abnormalities in chemokine levels in schizophrenia and their clinical correlates. Schizophr Res. 2016; 181:63-69. PMC: 5357211. DOI: 10.1016/j.schres.2016.09.019. View

20.

Koper O, Kaminska J, Sawicki K, Kemona H . CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med. 2018; 27(6):849-856. DOI: 10.17219/acem/68846. View