Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

Yingbo Huang; Yuting Shan; Weijie Zhang; Adam M. Lee; Feng Li; Barbara E. Stranger; R. Stephanie Huang

doi:10.1038/s41467-023-35808-6

Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

Yingbo Huang, Yuting Shan, Weijie Zhang, Adam M. Lee, Feng Li, Barbara E. Stranger, R. Stephanie Huang

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

Abstract

Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.

Original language	English (US)
Article number	175
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-35808-6
State	Published - Dec 2023

Bibliographical note

Funding Information:
This study is supported by NIH/NCI Grants R01CA229618 (to R.S.H. and B.E.S.) and NIH Grants R01HG011405 (to B.E.S.). We thank the donors and their families for their generous gifts of biospecimens to the GTEx research project. We thank Dr. James Fisher in Clinical Pharmacology Analytical Services (CPAS) for his help in developing the LC-MS assay. We thank individuals at the University of Minnesota for technical support in executing experiments. We thank the 3M Science and Technology Fellowship, Bighley Graduate Fellowship, A-PReP Scholarship (UMN-CTSI) for their support.

Funding Information:
This study is supported by NIH/NCI Grants R01CA229618 (to R.S.H. and B.E.S.) and NIH Grants R01HG011405 (to B.E.S.). We thank the donors and their families for their generous gifts of biospecimens to the GTEx research project. We thank Dr. James Fisher in Clinical Pharmacology Analytical Services (CPAS) for his help in developing the LC-MS assay. We thank individuals at the University of Minnesota for technical support in executing experiments. We thank the 3M Science and Technology Fellowship, Bighley Graduate Fellowship, A-PReP Scholarship (UMN-CTSI) for their support.

Publisher Copyright:
© 2023, The Author(s).

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Research Support, N.I.H., Extramural

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title = "Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes",

abstract = "Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.",

author = "Yingbo Huang and Yuting Shan and Weijie Zhang and Lee, {Adam M.} and Feng Li and Stranger, {Barbara E.} and Huang, {R. Stephanie}",

note = "Funding Information: This study is supported by NIH/NCI Grants R01CA229618 (to R.S.H. and B.E.S.) and NIH Grants R01HG011405 (to B.E.S.). We thank the donors and their families for their generous gifts of biospecimens to the GTEx research project. We thank Dr. James Fisher in Clinical Pharmacology Analytical Services (CPAS) for his help in developing the LC-MS assay. We thank individuals at the University of Minnesota for technical support in executing experiments. We thank the 3M Science and Technology Fellowship, Bighley Graduate Fellowship, A-PReP Scholarship (UMN-CTSI) for their support. Funding Information: This study is supported by NIH/NCI Grants R01CA229618 (to R.S.H. and B.E.S.) and NIH Grants R01HG011405 (to B.E.S.). We thank the donors and their families for their generous gifts of biospecimens to the GTEx research project. We thank Dr. James Fisher in Clinical Pharmacology Analytical Services (CPAS) for his help in developing the LC-MS assay. We thank individuals at the University of Minnesota for technical support in executing experiments. We thank the 3M Science and Technology Fellowship, Bighley Graduate Fellowship, A-PReP Scholarship (UMN-CTSI) for their support. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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doi = "10.1038/s41467-023-35808-6",

language = "English (US)",

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AU - Li, Feng

AU - Stranger, Barbara E.

AU - Huang, R. Stephanie

N1 - Funding Information: This study is supported by NIH/NCI Grants R01CA229618 (to R.S.H. and B.E.S.) and NIH Grants R01HG011405 (to B.E.S.). We thank the donors and their families for their generous gifts of biospecimens to the GTEx research project. We thank Dr. James Fisher in Clinical Pharmacology Analytical Services (CPAS) for his help in developing the LC-MS assay. We thank individuals at the University of Minnesota for technical support in executing experiments. We thank the 3M Science and Technology Fellowship, Bighley Graduate Fellowship, A-PReP Scholarship (UMN-CTSI) for their support. Funding Information: This study is supported by NIH/NCI Grants R01CA229618 (to R.S.H. and B.E.S.) and NIH Grants R01HG011405 (to B.E.S.). We thank the donors and their families for their generous gifts of biospecimens to the GTEx research project. We thank Dr. James Fisher in Clinical Pharmacology Analytical Services (CPAS) for his help in developing the LC-MS assay. We thank individuals at the University of Minnesota for technical support in executing experiments. We thank the 3M Science and Technology Fellowship, Bighley Graduate Fellowship, A-PReP Scholarship (UMN-CTSI) for their support. Publisher Copyright: © 2023, The Author(s).

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N2 - Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.

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Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

Abstract

Bibliographical note

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