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

Producción científica: Article › revisión exhaustiva

36 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	40-46
Número de páginas	7
Publicación	Schizophrenia Research
Volumen	98
N.º	1-3
DOI	https://doi.org/10.1016/j.schres.2007.10.003
Estado	Published - ene 2008

Nota bibliográfica

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.

Financiación

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. 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.

Financiadores	Número del financiador
Department of Cell and Molecular Neurobiology, Bristol-Myers-Squibb
Eli Lilly Research Foundation
Roche Molecular Systems, Inc.
National Institutes of Health (NIH)	1 R43 MH073291-01
Eli Lilly and Company
Janssen Biotech
National Alliance for Research on Schizophrenia and Depression

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Psychiatry and Mental health
Biological Psychiatry

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10.1016/j.schres.2007.10.003

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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",

author = "\{de Leon\}, Jose and Correa, \{Juan Carlos\} and Gualberto Rua{\~n}o and Andreas Windemuth and Arranz, \{Maria J.\} and Diaz, \{Francisco J.\}",

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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KW - Cholesterol

KW - Hypercholesterolemia

KW - Hypertriglyceridemia

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

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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