Complement 3 and metabolic syndrome induced by clozapine: a cross-sectional study and retrospective cohort analysis

Metabolic syndrome (MetS) is considered to be an adverse effect of long-term treatment with atypical antipsychotics, particularly clozapine. There is strong evidence that the activation of inflammatory pathways interferes with normal metabolism and contributes to the development of MetS. C3, which is an inflammation molecule, has been reported to be associated with MetS. Because C3 is a heritable trait, we accordingly hypothesized that the gene encoding C3 (C3) would be a candidate gene for inter-individual variation in clozapine-induced MetS. We recruited 576 schizophrenia patients taking clozapine and measured the serum levels of fasting metabolic parameters. We then examined C3 mRNA and genotyped seven polymorphisms in C3. The expression quantitative trait locus (eQTL) data available for tissues were extracted by the Genotype-Tissue Expression Portal. A total of 105 patients' medical records were retrospectively reviewed to obtain the metabolic parameters during the initial 2-year clozapine treatment. The relative expression levels of C3 mRNA in patients with MetS were significantly higher than in those without MetS (P=0.02). C3 single-nucleotide polymorphism (SNP) rs2277984 was marginally associated with MetS (allelic P=0.06, odds ratio=1.36, 95% confidence interval (CI): 1.07-1.72). We found a significant association of rs2277984 with fasting triglyceride (TG) levels (P=0.004). Further, eQTL analysis revealed that rs2277984 regulates C3 expression in the liver (P=0.002). Similar results were found in the retrospective cohort analysis. The receiver operating characteristic curve showed a significant effect of the rs2277984 G allele on the percentage change of TG levels, with an area under the curve of 0.71 (95% CI: 0.60-0.81). C3 is likely to enhance TG accumulation and to confer susceptibility to clozapine-induced MetS. The C3 SNP rs2277984 may be a potential biomarker for predicting MetS risk in patients receiving clozapine treatment.