Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels

Jose de Leon; Juan Carlos Correa; Gualberto Ruaño; Andreas Windemuth; Maria J. Arranz; Francisco J. Diaz

doi:10.1016/j.schres.2007.10.003

Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels

Jose de Leon, Juan Carlos Correa, Gualberto Ruaño, Andreas Windemuth, Maria J. Arranz, Francisco J. Diaz

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

The goal of this study was to select some genes that may serve as good candidates for future studies of the direct effects (not explained by obesity) of some antipsychotics on hyperlipidemia. A search for single-nucleotide polymorphisms (SNPs) that may be associated with these direct effects was conducted. From a published cross-sectional sample, 357 patients on antipsychotics were genotyped using a DNA microarray with 384 SNPs. A total of 165 patients were taking olanzapine, quetiapine or chlorpromazine which may directly cause hypertriglyceridemia or hypercholesterolemia. Another 192 patients taking other antipsychotics were controls. A two-stage statistical analysis that included loglinear and logistic models was developed to select SNPs blindly. In a third stage, physiological knowledge was used to select promising SNPs. Known physiological mechanisms were supported for 3 associations found in patients taking olanzapine, quetiapine or chlorpromazine [acetyl-coenzyme A carboxylase α SNP (rs4072032) in the hypertriglyceridemia model, and for the neuropeptide Y (rs1468271) and ACCβ, (rs2241220) in the hypercholesterolemia model]. These genes may be promising candidates for studies of the direct effects of some antipsychotics on hyperlipidemia.

Original language	English
Pages (from-to)	40-46
Number of pages	7
Journal	Schizophrenia Research
Volume	98
Issue number	1-3
DOIs	https://doi.org/10.1016/j.schres.2007.10.003
State	Published - Jan 2008

Bibliographical note

Funding Information:
No pharmaceutical organizations had any role in the writing of this paper for publication. The original pharmacogenetic study at the University of Kentucky Mental Health Research Center was supported by several sources: a researcher-initiated grant from Roche Molecular Systems, Inc., a NARSAD Independent Investigator Award to Jose de Leon, M.D., and internal resources. Genotyping was conducted at Genomas, Hartford, CT by Mohan Kocherla, M.S. Statistical analyses were conducted without additional external support.

Funding Information:
In the past three years, Jose de Leon, M.D., has been on the advisory board of Roche Molecular Systems, Inc., and Bristol Myers and Squibb; he received investigator-initiated grants from Roche Molecular Systems, Inc., and Eli Lilly Research Foundation; he has lectured twice supported by Eli Lilly, twice by Janssen, and six times by Roche Molecular Systems, Inc. Juan Carlos Correa, Ph.D., has no conflict of interest. Gualberto Ruaño, M.D., Ph.D., and Andreas Windemuth, Ph.D., work at Genomas, Inc, a pharmacogenetic company interested in the metabolic syndrome and supported by a NIH Small Business Innovation Research Grant 1 R43 MH073291-01 “Gene Markers: Antipsychotic-Induced Metabolic Syndrome.” Maria J. Arranz, Ph.D., is a consultant for the company TheraGenetics (UK), and actively collaborates with the company LGC (UK) in the development of genetic tests. Dr. Arranz has received consultancy money from LGC. In the past three years, Francisco J. Diaz, Ph.D., has been a statistical consultant for an investigator-initiated Eli Lilly Research Foundation grant in which Dr. de Leon was a co-investigator.

Keywords

Acetyl-coenzyme A carboxylase
Antipsychotics
Chlorpromazine
Cholesterol
Hypercholesterolemia
Hypertriglyceridemia
Lipids
Metabolic syndrome
Neuropeptide Y
Olanzapine
Quetiapine
Triglycerides

ASJC Scopus subject areas

Psychiatry and Mental health
Biological Psychiatry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.schres.2007.10.003

Cite this

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title = "Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels",

abstract = "The goal of this study was to select some genes that may serve as good candidates for future studies of the direct effects (not explained by obesity) of some antipsychotics on hyperlipidemia. A search for single-nucleotide polymorphisms (SNPs) that may be associated with these direct effects was conducted. From a published cross-sectional sample, 357 patients on antipsychotics were genotyped using a DNA microarray with 384 SNPs. A total of 165 patients were taking olanzapine, quetiapine or chlorpromazine which may directly cause hypertriglyceridemia or hypercholesterolemia. Another 192 patients taking other antipsychotics were controls. A two-stage statistical analysis that included loglinear and logistic models was developed to select SNPs blindly. In a third stage, physiological knowledge was used to select promising SNPs. Known physiological mechanisms were supported for 3 associations found in patients taking olanzapine, quetiapine or chlorpromazine [acetyl-coenzyme A carboxylase α SNP (rs4072032) in the hypertriglyceridemia model, and for the neuropeptide Y (rs1468271) and ACCβ, (rs2241220) in the hypercholesterolemia model]. These genes may be promising candidates for studies of the direct effects of some antipsychotics on hyperlipidemia.",

keywords = "Acetyl-coenzyme A carboxylase, Antipsychotics, Chlorpromazine, Cholesterol, Hypercholesterolemia, Hypertriglyceridemia, Lipids, Metabolic syndrome, Neuropeptide Y, Olanzapine, Quetiapine, Triglycerides",

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note = "Funding Information: No pharmaceutical organizations had any role in the writing of this paper for publication. The original pharmacogenetic study at the University of Kentucky Mental Health Research Center was supported by several sources: a researcher-initiated grant from Roche Molecular Systems, Inc., a NARSAD Independent Investigator Award to Jose de Leon, M.D., and internal resources. Genotyping was conducted at Genomas, Hartford, CT by Mohan Kocherla, M.S. Statistical analyses were conducted without additional external support. Funding Information: In the past three years, Jose de Leon, M.D., has been on the advisory board of Roche Molecular Systems, Inc., and Bristol Myers and Squibb; he received investigator-initiated grants from Roche Molecular Systems, Inc., and Eli Lilly Research Foundation; he has lectured twice supported by Eli Lilly, twice by Janssen, and six times by Roche Molecular Systems, Inc. Juan Carlos Correa, Ph.D., has no conflict of interest. Gualberto Rua{\~n}o, M.D., Ph.D., and Andreas Windemuth, Ph.D., work at Genomas, Inc, a pharmacogenetic company interested in the metabolic syndrome and supported by a NIH Small Business Innovation Research Grant 1 R43 MH073291-01 “Gene Markers: Antipsychotic-Induced Metabolic Syndrome.” Maria J. Arranz, Ph.D., is a consultant for the company TheraGenetics (UK), and actively collaborates with the company LGC (UK) in the development of genetic tests. Dr. Arranz has received consultancy money from LGC. In the past three years, Francisco J. Diaz, Ph.D., has been a statistical consultant for an investigator-initiated Eli Lilly Research Foundation grant in which Dr. de Leon was a co-investigator. ",

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AU - Arranz, Maria J.

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AB - The goal of this study was to select some genes that may serve as good candidates for future studies of the direct effects (not explained by obesity) of some antipsychotics on hyperlipidemia. A search for single-nucleotide polymorphisms (SNPs) that may be associated with these direct effects was conducted. From a published cross-sectional sample, 357 patients on antipsychotics were genotyped using a DNA microarray with 384 SNPs. A total of 165 patients were taking olanzapine, quetiapine or chlorpromazine which may directly cause hypertriglyceridemia or hypercholesterolemia. Another 192 patients taking other antipsychotics were controls. A two-stage statistical analysis that included loglinear and logistic models was developed to select SNPs blindly. In a third stage, physiological knowledge was used to select promising SNPs. Known physiological mechanisms were supported for 3 associations found in patients taking olanzapine, quetiapine or chlorpromazine [acetyl-coenzyme A carboxylase α SNP (rs4072032) in the hypertriglyceridemia model, and for the neuropeptide Y (rs1468271) and ACCβ, (rs2241220) in the hypercholesterolemia model]. These genes may be promising candidates for studies of the direct effects of some antipsychotics on hyperlipidemia.

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KW - Lipids

KW - Metabolic syndrome

KW - Neuropeptide Y

KW - Olanzapine

KW - Quetiapine

KW - Triglycerides

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Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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