Dataset Information

Lack of Association between the IL6R Gene Asp358Ala Variant (rs2228145), IL-6 Plasma Levels, and Treatment Resistance in Chilean Schizophrenic Patients Treated with Clozapine.

ABSTRACT: Alterations in neuroinflammatory processes have been suggested to contribute to the development of Schizophrenia (SZ); one component of the inflammatory system that has been linked to this disorder is interleukin-6 (IL-6). The minor allele of rs2228145, a functional polymorphism in the IL-6 receptor gene, has been associated to elevated IL-6 plasma levels and increased inflammatory activity, making it an interesting candidate to study as a possible factor underlying clinical heterogeneity in SZ. We studied a sample of 100 patients undergoing treatment with clozapine. Their symptoms were quantified by Brief Psychotic Rating Scale; those with the lowest scores ("remitted") were compared with the highest ("clozapine treatment resistant"). We determined allelic frequencies for rs2228145 and IL-6 plasma levels. Our results do not support a role of IL-6 in response to treatment with clozapine. Further studies accounting for potential confounding factors are necessary.

SUBMITTER: Cavieres A

PROVIDER: S-EPMC6614962 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Lack of Association between the <i>IL6R</i> Gene Asp358Ala Variant (rs2228145), IL-6 Plasma Levels, and Treatment Resistance in Chilean Schizophrenic Patients Treated with Clozapine.

Cavieres Alvaro A Campos-Estrada Carolina C Moya Yanneth Y Maldonado Rocío R González-Vargas René R Bustamante María Leonor ML Moya Pablo R PR

Schizophrenia research and treatment 20190625

Alterations in neuroinflammatory processes have been suggested to contribute to the development of Schizophrenia (SZ); one component of the inflammatory system that has been linked to this disorder is interleukin-6 (IL-6). The minor allele of rs2228145, a functional polymorphism in the IL-6 receptor gene, has been associated to elevated IL-6 plasma levels and increased inflammatory activity, making it an interesting candidate to study as a possible factor underlying clinical heterogeneity in SZ. ...[more]

PMID: 31341681

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Project description:Abstract Background: Benign ethnic neutropenia (BEN) is the occurrence of absolute neutrophil counts (ANC) of less than 1500 cells/mm3 observed in 10% to 30% of African and Middle Eastern ancestry individuals with no increased susceptibility to pyogenic infections. Recent evidence implicates polymorphism in the Duffy Antigen Receptor for Chemokines gene (DARC) in BEN persons of African descent. Until mid-2015 in the United States, the FDA clozapine treatment guidelines for ANC monitoring were based on normative ANC values in European ancestry populations without considerations for BEN. Compared with Caucasians, African Americans are less likely to be initiated on clozapine and their treatment twice as likely to be discontinued for neutropenia. Gathering data indicate no increased agranulocytosis risk in clozapine-treated BEN individuals. Advancing knowledge of BEN pathophysiology could reduce a substantial barrier to clozapine treatment in African-American patients. Methods: We examined ANC data collected on a sample of 136 schizophrenia and 33 healthy control Yoruba participants recruited at the Federal Neuropsychiatric Hospital Yaba, Lagos. Exclusion criteria included medical conditions that could affect white blood cell counts. In the patient group, 100 had been on stable clozapine treatment (>6 months). In a subgroup of participants (n = 69), we assayed the regulatory variant (rs2814778) in the promoter of DARC (DARC -46T > C) implicated in low neutrophil counts in African-ancestry populations. Results: The sample consisted of 88 females and 81 males. Sex was not different between schizophrenia and control groups (P = .3). Age differed between schizophrenia (mean [SD], 40.15 [13.15] years) and controls (mean [SD], 29.12 [5.08] years; P < .001). The sample mean ANC was 2,557/mm3 (range 800 to 6,970); with 31% and 11% showing ANC below 2000 and 1500/mm3, respectively. The mean daily clozapine dose was 224?mg. Clozapine-treated patients had a significantly higher mean ANC (2777/mm3 [0.97]) compared with controls and non-clozapine treated patients (2238/mm3 [0.88]; P < .001). All 69 individuals assayed for rs2814778 were homozygous for the Duffy-null allele (DARC -46T > C). Conclusion: The results are consistent with reported rates of BEN in African populations, supports the safety of clozapine monitoring using lower ANC levels in BEN populations, and demonstrates the common occurrence of the African-derived “null” DARC gene variant in this sample.

Project description:Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes.Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23).Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo.Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

Project description:The levels of plasma interleukin 6 and its soluble receptors were found to be elevated in subjects with cardiovascular diseases, which points to amplification of the IL-6-mediated trans-signaling pathway in cells and the development of chronic inflammation. The allelic variation in the rs2228145 IL6R gene is associated with a change in the contents of the soluble and membrane-bound receptor forms mediating the biological activity of IL-6. Cytokine IL-6 is involved in the development of endothelial dysfunction by regulating the expression of the VCAM1 and ICAM1 genes, encoding intercellular adhesion molecules. Prior to this work, no data on the association of essential arterial hypertension (EAH) with rs2228145 allelic variations of the IL6R gene have been reported. The aim of our work was to study the relationship of the carriership of rs2228145 (A > C) allelic variations with the development of EAH and the VCAM1 and ICAM1 transcript levels. We analyzed samples of DNA isolated from the whole blood of 148 healthy donors and 152 patients with EAH (stages I-II). The genotyping was performed by PCR-RFLP. The level of transcripts in peripheral blood leukocytes (PBL) was assessed by real-time PCR. Differences in the frequency distributions of rs2228145 (A > C) genotypes between the control group and the group of patients with EAH (χ2 = 9.303) were found. The frequency of the CC genotype in EAH patients was higher than in healthy people (0.191 and 0.095, respectively). The risk of EAH (I-II stages) development was shown to be 2.3 times higher in CC genotype carriers as compared to individuals with other genotypes (OR = 2.257, 95 % confidence interval 1.100-4.468). The levels of VCAM1 and ICAM1 gene transcripts in PBL of patients with EAH were significantly higher than in healthy people. The level of ICAM1 gene transcripts was almost 4 times higher in patients with CC genotype. The Kruskal-Wallis analysis of variance revealed an effect of rs2228145 (A > C) genotype on the transcriptional activity of ICAM1, which argues for its role in the pathogenesis of endothelial dysfunction and essential hypertension.

Dataset Information

Lack of Association between the IL6R Gene Asp358Ala Variant (rs2228145), IL-6 Plasma Levels, and Treatment Resistance in Chilean Schizophrenic Patients Treated with Clozapine.

Publications

Lack of Association between the <i>IL6R</i> Gene Asp358Ala Variant (rs2228145), IL-6 Plasma Levels, and Treatment Resistance in Chilean Schizophrenic Patients Treated with Clozapine.

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