TLR4 Polymorphisms (T399I/D299G) Association with Schizophrenia and Bipolar Disorder in a Tunisian Population

• Published in: Biochemical genetics Vol. 62; no. 4; pp. 2418 - 2436
• Main Authors: Aflouk, Youssef, Saoud, Hana, Inoubli, Oumaima, Yacoub, Saloua, Zaafrane, Ferid, Gaha, Lotfi, Bel Hadj Jrad, Besma
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2024; Springer Nature B.V
• Subjects: Adult; Alleles; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bipolar disorder; Bipolar Disorder - genetics; Case-Control Studies; Female; Gene Frequency; Genetic factors; Genetic Predisposition to Disease; Genotype; Haplotypes; Human Genetics; Humans; Male; Medical Microbiology; Mental disorders; Middle Aged; Original Article; Polymorphism, Single Nucleotide; Population (statistical); Population genetics; Psychosis; Regression models; Schizophrenia; Schizophrenia - genetics; Statistical analysis; Statistical models; Subgroups; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-like receptors; Tunisia; Zoology; Tunisia; Schizophrenia; Bipolar disorder; D299G; TLR4; T399I
• ISSN: 0006-2928; 1573-4927; 1573-4927
• DOI: 10.1007/s10528-023-10553-z

Immune dysregulation has been widely described in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BD). Particularly, TLR4-altered activation was proposed as one of the underlying processes of psychosis onset. Since TLR4 activation was altered by T399I and D299G polymorphisms, we hypothesized that those variants could present common genetic factors of SCZ and BD. A total of 293 healthy volunteers and 335 psychotic patients were genotyped using PCR–RFLP. Genotype, allele, and haplotype distribution between controls and patients were evaluated according to clinical parameters. Statistical analyses were adjusted by logistic regression. In dominant model, T399I CT + TT and allele frequency were significantly higher in controls compared to psychotic population ( p  = 0.004, p  = 0.002, respectively), SCZ ( p  = 0.02, p  = 0.01, respectively), and BD ( p  = 0.03, p = 0.02, respectively). Similarly, D299G AG + GG and allele frequency were significantly higher in controls compared to psychotic population ( p  = 0.04, p  = 0.04, respectively) and SCZ ( p  = 0.04, p = 0.03, respectively). T399I CT + TT and T allele were overrepresented in controls compared to paranoid subgroup (P adjusted  = 0.04, p  = 0.04, respectively) and type I BD ( p  = 0.04). Moreover, T399I and D299G were less prevalent in SCZ late-onset age ( p  = 0.03, p  = 0.02, respectively). TA haplotype was associated with protection from psychoses ( p  = 0.02) and particularly from schizophrenia ( p  = 0.04). In conclusion, TLR4 polymorphisms could present a preventive genetic background against psychoses onset in a Tunisian population. While T399I could be associated with protection against SCZ and BD, presenting an overlapping genetic factor between those psychoses, D299G was suggested to be associated with protection only from schizophrenia.