Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study

BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Lingsi Zeng [verfasserIn] Honggang Lv [verfasserIn] Juan Li [verfasserIn] Ranran Xue [verfasserIn] Xia Liu [verfasserIn] Cong Zhou [verfasserIn] Hao Yu [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Mendelian randomization nicotine consumption alcohol consumption coffee consumption clozapine concentration

Übergeordnetes Werk:	In: Frontiers in Psychiatry - Frontiers Media S.A., 2010, 13(2022)
Übergeordnetes Werk:	volume:13 ; year:2022

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fpsyt.2022.1002235

Katalog-ID:	DOAJ032334796

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520			\|a BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients.
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allfields	10.3389/fpsyt.2022.1002235 doi (DE-627)DOAJ032334796 (DE-599)DOAJc755763f76d44be99cb90cf7e80b6be4 DE-627 ger DE-627 rakwb eng RC435-571 Lingsi Zeng verfasserin aut Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients. Mendelian randomization nicotine consumption alcohol consumption coffee consumption clozapine concentration Psychiatry Honggang Lv verfasserin aut Juan Li verfasserin aut Ranran Xue verfasserin aut Xia Liu verfasserin aut Cong Zhou verfasserin aut Hao Yu verfasserin aut In Frontiers in Psychiatry Frontiers Media S.A., 2010 13(2022) (DE-627)631498796 (DE-600)2564218-2 16640640 nnns volume:13 year:2022 https://doi.org/10.3389/fpsyt.2022.1002235 kostenfrei https://doaj.org/article/c755763f76d44be99cb90cf7e80b6be4 kostenfrei https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1002235/full kostenfrei https://doaj.org/toc/1664-0640 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
spelling	10.3389/fpsyt.2022.1002235 doi (DE-627)DOAJ032334796 (DE-599)DOAJc755763f76d44be99cb90cf7e80b6be4 DE-627 ger DE-627 rakwb eng RC435-571 Lingsi Zeng verfasserin aut Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients. Mendelian randomization nicotine consumption alcohol consumption coffee consumption clozapine concentration Psychiatry Honggang Lv verfasserin aut Juan Li verfasserin aut Ranran Xue verfasserin aut Xia Liu verfasserin aut Cong Zhou verfasserin aut Hao Yu verfasserin aut In Frontiers in Psychiatry Frontiers Media S.A., 2010 13(2022) (DE-627)631498796 (DE-600)2564218-2 16640640 nnns volume:13 year:2022 https://doi.org/10.3389/fpsyt.2022.1002235 kostenfrei https://doaj.org/article/c755763f76d44be99cb90cf7e80b6be4 kostenfrei https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1002235/full kostenfrei https://doaj.org/toc/1664-0640 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
allfields_unstemmed	10.3389/fpsyt.2022.1002235 doi (DE-627)DOAJ032334796 (DE-599)DOAJc755763f76d44be99cb90cf7e80b6be4 DE-627 ger DE-627 rakwb eng RC435-571 Lingsi Zeng verfasserin aut Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients. Mendelian randomization nicotine consumption alcohol consumption coffee consumption clozapine concentration Psychiatry Honggang Lv verfasserin aut Juan Li verfasserin aut Ranran Xue verfasserin aut Xia Liu verfasserin aut Cong Zhou verfasserin aut Hao Yu verfasserin aut In Frontiers in Psychiatry Frontiers Media S.A., 2010 13(2022) (DE-627)631498796 (DE-600)2564218-2 16640640 nnns volume:13 year:2022 https://doi.org/10.3389/fpsyt.2022.1002235 kostenfrei https://doaj.org/article/c755763f76d44be99cb90cf7e80b6be4 kostenfrei https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1002235/full kostenfrei https://doaj.org/toc/1664-0640 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
allfieldsGer	10.3389/fpsyt.2022.1002235 doi (DE-627)DOAJ032334796 (DE-599)DOAJc755763f76d44be99cb90cf7e80b6be4 DE-627 ger DE-627 rakwb eng RC435-571 Lingsi Zeng verfasserin aut Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients. Mendelian randomization nicotine consumption alcohol consumption coffee consumption clozapine concentration Psychiatry Honggang Lv verfasserin aut Juan Li verfasserin aut Ranran Xue verfasserin aut Xia Liu verfasserin aut Cong Zhou verfasserin aut Hao Yu verfasserin aut In Frontiers in Psychiatry Frontiers Media S.A., 2010 13(2022) (DE-627)631498796 (DE-600)2564218-2 16640640 nnns volume:13 year:2022 https://doi.org/10.3389/fpsyt.2022.1002235 kostenfrei https://doaj.org/article/c755763f76d44be99cb90cf7e80b6be4 kostenfrei https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1002235/full kostenfrei https://doaj.org/toc/1664-0640 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
allfieldsSound	10.3389/fpsyt.2022.1002235 doi (DE-627)DOAJ032334796 (DE-599)DOAJc755763f76d44be99cb90cf7e80b6be4 DE-627 ger DE-627 rakwb eng RC435-571 Lingsi Zeng verfasserin aut Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients. Mendelian randomization nicotine consumption alcohol consumption coffee consumption clozapine concentration Psychiatry Honggang Lv verfasserin aut Juan Li verfasserin aut Ranran Xue verfasserin aut Xia Liu verfasserin aut Cong Zhou verfasserin aut Hao Yu verfasserin aut In Frontiers in Psychiatry Frontiers Media S.A., 2010 13(2022) (DE-627)631498796 (DE-600)2564218-2 16640640 nnns volume:13 year:2022 https://doi.org/10.3389/fpsyt.2022.1002235 kostenfrei https://doaj.org/article/c755763f76d44be99cb90cf7e80b6be4 kostenfrei https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1002235/full kostenfrei https://doaj.org/toc/1664-0640 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
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authorswithroles_txt_mv	Lingsi Zeng @@aut@@ Honggang Lv @@aut@@ Juan Li @@aut@@ Ranran Xue @@aut@@ Xia Liu @@aut@@ Cong Zhou @@aut@@ Hao Yu @@aut@@
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Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P &gt; 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. 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title	Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study
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title_full	Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study
author_sort	Lingsi Zeng
journal	Frontiers in Psychiatry
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author_browse	Lingsi Zeng Honggang Lv Juan Li Ranran Xue Xia Liu Cong Zhou Hao Yu
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title_sort	cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: a mendelian randomization study
callnumber	RC435-571
title_auth	Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study
abstract	BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients.
abstractGer	BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients.
abstract_unstemmed	BackgroundClozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established.MethodsSeveral genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium’s dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses.ResultsGenetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (β = –0.14, P = 4.53E-04) concentrations and norclozapine concentrations (β = –0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (β = –0.42, P = 1.70E-14), norclozapine concentrations (β = –0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (β = –0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism.ConclusionOur investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients.
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title_short	Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study
url	https://doi.org/10.3389/fpsyt.2022.1002235 https://doaj.org/article/c755763f76d44be99cb90cf7e80b6be4 https://www.frontiersin.org/articles/10.3389/fpsyt.2022.1002235/full https://doaj.org/toc/1664-0640
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author2	Honggang Lv Juan Li Ranran Xue Xia Liu Cong Zhou Hao Yu
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up_date	2024-07-04T00:50:13.068Z
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