Association between SREBF2 gene polymorphisms and metabolic syndrome in clozapine-treated patients with schizophrenia

Yang, Lin; Chen, Jianhua; Liu, Dengtang; Yu, Shunying; Cong, Enzhao; Li, Yan; Wu, Hongmei; Ye, Ying; Zuo, Sai; Wang, Yan; Liang, Shiqiao; Shi, Yongyong; Shi, Sheng; Xu, Yifeng

doi:10.1016/j.pnpbp.2014.08.015

Cited by 24 publications

(11 citation statements)

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“…In details, concerning MetS, a significant difference between the two genotypes emerged, showing that G/G homozygous subjects have higher triglycerides, as well as an increased prevalence of MetS, compared to carriers of the A allele. It is known that SREBPs are implicated in the synthesis of fatty acids, triglycerides, and cholesterol in all organs (49) and our finding supports previous literature showing an association between the G allele and the risk to develop Type II Diabetes, as well as other metabolic disturbances in both non-psychiatric populations and patients with schizophrenia (50, 51). Regarding cognitive functions, the role of SREBF on cognition is less explored and far from being clear.…”

Section: Discussionsupporting

confidence: 92%

Improving Cognition to Increase Treatment Efficacy in Schizophrenia: Effects of Metabolic Syndrome on Cognitive Remediation's Outcome

et al. 2018

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Cognitive impairment, typically more severe in treatment resistant patients, is considered a hallmark of schizophrenia and the prime driver of functional disability. Recent evidence suggests that metabolic syndrome may contribute to cognitive deficits in schizophrenia, possibly through shared underlying mechanisms. However, results are still contradictory and no study has so far examined the influence of metabolic syndrome on cognitive outcome after cognitive remediation therapy (CRT). Based on these premises, this study aims to investigate the relationship between metabolic syndrome and cognition, specifically considering cognitive outcome after treatment. Secondary objectives include the analysis of the association between cognitive impairment and psychopathological status and, in a subgroup of patients, the evaluation of the effect of Sterol Regulatory Element Binding Transcription Factor 1 (SREBF-1) rs11868035 genetic polymorphism, previously associated with metabolic alterations, on both cognition and metabolic syndrome. One-hundred seventy-two outpatients with schizophrenia were assessed for metabolic parameters and neurocognitive measures and 138 patients, who completed CRT, were re-evaluated for cognition. A subsample of 51 patients was also genotyped for rs11868035 from peripheral blood sample. Results show a negative impact of metabolic syndrome on executive functions and global cognitive outcome after CRT. Data also revealed a significant effect of SREBF-1 polymorphism, with a higher prevalence of metabolic syndrome and worse processing speed performance among G/G homozygous subjects, compared the A allele carriers. Overall these findings support the hypothesis that metabolic alterations may hamper the capacity to restore cognitive deficits, as well as they highlight the need to further explore possible converging mechanisms underlying both cognitive and metabolic dysfunction. At the clinical level, results point to the importance of a comprehensive assessment including the metabolic status of patients and of individualized strategies addressing metabolic dysfunction in order to potentiate treatment outcome in schizophrenia.

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Section: Discussionsupporting

confidence: 92%

Improving Cognition to Increase Treatment Efficacy in Schizophrenia: Effects of Metabolic Syndrome on Cognitive Remediation's Outcome

et al. 2018

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“…A small number of studies have identified a link between genetic markers in genes involved in cholesterol metabolism and adverse effects of antipsychotic treatment, helping to further substantiate these findings (Chowdhury et al, 2011;Yang et al, 2016Yang et al, , 2015. Additional studies suggest that alterations in cholesterol metabolism by antipsychotic drugs may contribute to the beneficial effects in treating psychosis.…”

Section: Discussionmentioning

confidence: 96%

Integrative genomic strategies applied to a lymphoblast cell line model reveal specific transcriptomic signatures associated with clozapine response

Ori

Wang

Pulit

et al. 2020

Preprint

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Clozapine is an important antipsychotic drug. However, its use is often accompanied by metabolic adverse effects and, in rare instances, agranulocytosis. The molecular mechanisms underlying these adverse events are unclear. To gain more insights into the response to clozapine at the molecular level, we exposed lymphoblastoid cell lines (LCLs) to increasing concentrations of clozapine and measured genome-wide gene expression and DNA methylation profiles. We observed robust and significant changes in gene expression levels due to clozapine (n = 463 genes at FDR < 0.05) affecting cholesterol and cell cycle pathways. At the level of DNA methylation, we find significant changes upstream of the LDL receptor, in addition to global enrichments of regulatory, immune and developmental pathways. By integrating these data with human tissue gene expression levels obtained from the Genotype-Tissue Expression project (GTEx), we identified specific tissues, including liver and several tissues involved in immune, endocrine and metabolic functions, that clozapine treatment may disproportionately affect. Notably, differentially expressed genes were not enriched for genome-wide disease risk of schizophrenia or for known psychotropic drug targets. However, we did observe a nominally significant association of genetic signals related to total cholesterol and low-density lipoprotein levels. Together, these results shed light on the biological mechanisms through which clozapine functions. The observed associations with cholesterol pathways, its genetic architecture and specific tissue effects may be indicative of the metabolic adverse effects observed in clozapine users. LCLs may thus serve as a useful tool to study these molecular mechanisms further.

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“…Furthermore, the G595A polymorphism of SREBP-2 has also been shown to be associated with intima media thickness in asymptomatic hypercholesterolemic men [ 32 ]. Another study provided evidence for the association between the SNPs rs1052717 and rs2267443 in SREBP-2 and metabolic syndrome in schizophrenic patients treated with clozapine [ 33 ]. In addition, the functional SNP rs133291 C/T in the SREBP-2 gene has been linked to serum LDL-C [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Association of genetic variations in the lipid regulatory pathway genes FBXW7 and SREBPs with coronary artery disease among Han Chinese and Uygur Chinese populations in Xinjiang, China

et al. 2017

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BackgroundHyperlipidemia is a major risk factor for coronary artery disease (CAD). The current study was designed to explore the possible correlation between single nucleotide polymorphisms (SNPs) in the lipid homeostasis regulatory genes F-box and WD repeat domain–containing 7 (FBXW7) and sterol regulatory element-binding proteins (SREBPs) with CAD among Han Chinese and Uygur Chinese populations in Xinjiang, China.ResultsIn the Uygur Chinese population, rs9902941 in SREBP-1 and rs10033601 in FBXW7 were found to be associated with CAD in a recessive model (TT vs. CT + CC, P = 0.032; GG vs. AG + AA, P = 0.010, respectively), and rs7288536 in SREBP-2 was found to be associated with CAD in an additive model (CT vs. CC + TT, P = 0.045). The difference was statistically significant in the Uygur Chinese population after multivariate adjustments [Odds ratio (OR) = 1.803, 95% confidence interval (CI): 1.036~3.137, P = 0.037; OR = 1.628, 95% CI: 1.080~2.454, P = 0.020; OR = 1.368; and 95% CI: 1.018~1.837, P = 0.037, respectively]. There were also significant interactions between the above-mentioned models in the Uygur Chinese population. However, these relationships were not observed before or after multivariate adjustment in the Han Chinese population.Materials and MethodsA total of 1,312 Han Chinese (650 CAD patients and 662 controls) and 834 Uygur Chinese (414 CAD patients and 420 controls) were enrolled in this case-control study. Three SNPs (rs9902941 in SREBP-1, rs7288536 in SREBP-2 and rs10033601 in FBXW7) were selected and genotyped using the improved multiplex ligase detection reaction (iMLDR) method.ConclusionsThe results of this study indicate that variations in the lipid regulatory pathway genes FBXW7 and SREBPs (rs9902941 in SREBP-1, rs7288536 in SREBP-2 and rs10033601 in FBXW7) are associated with CAD in the Uygur Chinese population in Xinjiang, China.

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Association between SREBF2 gene polymorphisms and metabolic syndrome in clozapine-treated patients with schizophrenia

Cited by 24 publications

References 35 publications

Improving Cognition to Increase Treatment Efficacy in Schizophrenia: Effects of Metabolic Syndrome on Cognitive Remediation's Outcome

Improving Cognition to Increase Treatment Efficacy in Schizophrenia: Effects of Metabolic Syndrome on Cognitive Remediation's Outcome

Integrative genomic strategies applied to a lymphoblast cell line model reveal specific transcriptomic signatures associated with clozapine response

Association of genetic variations in the lipid regulatory pathway genes FBXW7 and SREBPs with coronary artery disease among Han Chinese and Uygur Chinese populations in Xinjiang, China

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