Pharmacogenomics of Sterol Synthesis and Statin Use in Schizophrenia Subjects Treated with Antipsychotics

Abstract

Objective: Patients with schizophrenia treated with antipsychotics often develop metabolic side effects including dyslipidemia. Antipsychotics potentially upregulate gene expression of a lipid metabolism pathway protein called SREBP via SREB transcription factors (SREBFs). Genetic variation within SREBF may contribute to dyslipidemias and lipid medication efficacy within schizophrenia. Results: A cross-sectional study of 157 patients were genotyped for SREBF1 (rs11868035) and SREBF2 (rs1057217) variants, and assessed for fasting lipids. The cohort‘s mean age was 46.6 years, was 64% male and 86% were using atypical antipsychotics. When stratified by statin use, those receiving a statin and carrying the SREBF1 T allele exhibited higher total cholesterol levels (p = 0.01), triglyceride levels (p = 0.04) and low-density lipoprotein levels (p = 0.03). A regression analysis controlling for gender differences in lipids showed that the SREBF1 T allele and statin interaction remained only for total cholesterol levels (F[4,149] = 5.8; p < 0.0001). Conclusion: For schizophrenia individuals with the SREBF1 rs11868035 T allele, incomplete response to statin medications may be seen. Future investigations may allow for personalizing dyslipidemia treatment based on pharmacogenetics within schizophrenia.

Original submitted 18 December 2012; Revision submitted 12 August 2013

KEYWORDS::

• cholesterol
• pharmacogenomics
• schizophrenia
• SREBF
• statins

Financial & competing interests disclosure

The following sources were utilized for this publication: NIMH (R01MH082784, 2R01MH082784), NIH-NCCR, GCRC Program (UL1RR024986 and 2UL1TR000433), the Chemistry Core of the Michigan Diabetes Research and Training Center (NIH5P60 DK 20572). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The following sources were utilized for this publication: NIMH (R01MH082784, 2R01MH082784), NIH-NCCR, GCRC Program (UL1RR024986 and 2UL1TR000433), the Chemistry Core of the Michigan Diabetes Research and Training Center (NIH5P60 DK 20572). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.