Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans

Abstract Nicotine is inactivated by the polymorphic CYP2A6 enzyme to cotinine and then to 3′hydroxycotinine. The Nicotine Metabolite Ratio (NMR; 3′hydroxycotinine/cotinine) is a heritable nicotine metabolism biomarker, varies with sex and ancestry, and influences smoking cessation and disease risk....

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Autores principales:	Meghan J. Chenoweth, Lisa Sanderson Cox, Nikki L. Nollen, Jasjit S. Ahluwalia, Neal L. Benowitz, Caryn Lerman, Jo Knight, Rachel F. Tyndale
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aa651533193346aaa160147f48f32988
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spelling	oai:doaj.org-article:aa651533193346aaa160147f48f329882021-12-02T18:51:28ZAnalyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans10.1038/s41598-021-98883-z2045-2322https://doaj.org/article/aa651533193346aaa160147f48f329882021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98883-zhttps://doaj.org/toc/2045-2322Abstract Nicotine is inactivated by the polymorphic CYP2A6 enzyme to cotinine and then to 3′hydroxycotinine. The Nicotine Metabolite Ratio (NMR; 3′hydroxycotinine/cotinine) is a heritable nicotine metabolism biomarker, varies with sex and ancestry, and influences smoking cessation and disease risk. We conducted sex-stratified genome-wide association studies of the NMR in European American (EA) and African American (AA) smokers (NCT01314001, NCT00666978). In EA females (n = 389) and males (n = 541), one significant (P < 5e−8) chromosome 19 locus was found (top variant: rs56113850, CYP2A6 (intronic), for C vs. T: females: beta = 0.67, P = 7.5e−22, 21.8% variation explained; males: beta = 0.75, P = 1.2e−37, 26.1% variation explained). In AA females (n = 503) and males (n = 352), the top variant was found on chromosome 19 but differed by sex (females: rs11878604, CYP2A6 (~ 16 kb 3′), for C vs. T: beta = − 0.71, P = 6.6e−26, 16.2% variation explained; males: rs3865454, CYP2A6 (~ 7 kb 3′), for G vs. T: beta = 0.64, P = 1.9e−19, 18.9% variation explained). In AA females, a significant region was found on chromosome 12 (top variant: rs12425845: P = 5.0e−9, TMEM132C (~ 1 Mb 5′), 6.1% variation explained) which was not significant in AA males. In AA males, significant regions were found on chromosomes 6 (top variant: rs9379805: P = 4.8e−9, SLC17A2 (~ 8 kb 5′), 8.0% variation explained) and 16 (top variant: rs77368288: P = 3.5e−8, ZNF469 (~ 92 kb 5′), 7.1% variation explained) which were not significant in AA females. Further investigation of these associations outside of chromosome 19 is required, as they did not replicate. Understanding how sex and ancestry influence nicotine metabolism genetics may improve personalized approaches for smoking cessation and risk prediction for tobacco-related diseases.Meghan J. ChenowethLisa Sanderson CoxNikki L. NollenJasjit S. AhluwaliaNeal L. BenowitzCaryn LermanJo KnightRachel F. TyndaleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Meghan J. Chenoweth Lisa Sanderson Cox Nikki L. Nollen Jasjit S. Ahluwalia Neal L. Benowitz Caryn Lerman Jo Knight Rachel F. Tyndale Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans
description	Abstract Nicotine is inactivated by the polymorphic CYP2A6 enzyme to cotinine and then to 3′hydroxycotinine. The Nicotine Metabolite Ratio (NMR; 3′hydroxycotinine/cotinine) is a heritable nicotine metabolism biomarker, varies with sex and ancestry, and influences smoking cessation and disease risk. We conducted sex-stratified genome-wide association studies of the NMR in European American (EA) and African American (AA) smokers (NCT01314001, NCT00666978). In EA females (n = 389) and males (n = 541), one significant (P < 5e−8) chromosome 19 locus was found (top variant: rs56113850, CYP2A6 (intronic), for C vs. T: females: beta = 0.67, P = 7.5e−22, 21.8% variation explained; males: beta = 0.75, P = 1.2e−37, 26.1% variation explained). In AA females (n = 503) and males (n = 352), the top variant was found on chromosome 19 but differed by sex (females: rs11878604, CYP2A6 (~ 16 kb 3′), for C vs. T: beta = − 0.71, P = 6.6e−26, 16.2% variation explained; males: rs3865454, CYP2A6 (~ 7 kb 3′), for G vs. T: beta = 0.64, P = 1.9e−19, 18.9% variation explained). In AA females, a significant region was found on chromosome 12 (top variant: rs12425845: P = 5.0e−9, TMEM132C (~ 1 Mb 5′), 6.1% variation explained) which was not significant in AA males. In AA males, significant regions were found on chromosomes 6 (top variant: rs9379805: P = 4.8e−9, SLC17A2 (~ 8 kb 5′), 8.0% variation explained) and 16 (top variant: rs77368288: P = 3.5e−8, ZNF469 (~ 92 kb 5′), 7.1% variation explained) which were not significant in AA females. Further investigation of these associations outside of chromosome 19 is required, as they did not replicate. Understanding how sex and ancestry influence nicotine metabolism genetics may improve personalized approaches for smoking cessation and risk prediction for tobacco-related diseases.
format	article
author	Meghan J. Chenoweth Lisa Sanderson Cox Nikki L. Nollen Jasjit S. Ahluwalia Neal L. Benowitz Caryn Lerman Jo Knight Rachel F. Tyndale
author_facet	Meghan J. Chenoweth Lisa Sanderson Cox Nikki L. Nollen Jasjit S. Ahluwalia Neal L. Benowitz Caryn Lerman Jo Knight Rachel F. Tyndale
author_sort	Meghan J. Chenoweth
title	Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans
title_short	Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans
title_full	Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans
title_fullStr	Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans
title_full_unstemmed	Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans
title_sort	analyses of nicotine metabolism biomarker genetics stratified by sex in african and european americans
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/aa651533193346aaa160147f48f32988
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Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans

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