Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia

Abstract

Schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug  gene and drug  haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine-or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids.

Altered apolipoprotein C expression in association with cognition impairments and hippocampus volume in schizophrenia and bipolar disorder

“…Due to antipsychotic medications in SZ and mood stabilisers in BD, those patients have an increased risk for metabolic disturbances and altered lipid metabolism (Gibbons, Thomas, Scarr, & Dean, 2010), ultimately contributing to an increased risk for cardiovascular disease (Meyer et al, 2008). Several authors observed an association between Apo concentrations in patients receiving psychiatric medication (e.g., phenothiazines, olanzapine, risperidone) (Dean et al, 2008;Sasaki et al, 1985;Smith, Segman, Golcer-Dubner, Pavlov, & Lerer, 2008;Song et al, 2014). Therefore, we controlled for potential effects of the duration of drug treatment, the dosage of the current treatment, as well as BMI values on the protein concentrations.…”

Pharmacogenetics in schizophrenia: a review of clozapine studies

“…152 Polymorphisms in the apolipoprotein A-V (APOA5) and C-III (APOC3) genes, but not in LEP, showed an influence on triglyceride and cholesterol levels in patients treated with clozapine or olanzapine. 74 Agranulocytosis is a serious adverse effect associated with clozapine. Some studies showed strong associations between polymorphisms in genes of the major histocompatibility complex (HLA) and the occurrence of this adverse effect.…”

Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

“…Polymorphisms in the synaptic plasticity protein SNAP25, were also associated with weight gain [101,177]. Polymorphisms in apolipoproteins (APOE, APO5 and APOC3) and in GNB3, with roles in signaling pathways, were associated with antipsychoticinduced metabolic syndrome [129,[178][179][180]. Proteins involved in apoptosis were found to contribute to weight gain and movement disorders.…”