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.
Highlights
Cigarette smoking remains a major public health concern[1]
The vast majority of genome-wide significant (GWS) variants found in genome-wide association studies (GWASs) of the nicotine metabolite ratio (NMR) in smokers were found in the CYP2A6 region of chromosome 1924–28; these GWASs all controlled for sex
We further stratified our sex-based analyses by genetic ancestry, due to differences in population substructure as well as in the NMR; AA have lower NMR on average compared to EA8
Summary
Cigarette smoking remains a major public health concern[1]. Smoking behaviors, including the response to pharmacotherapy, differ between men and women. Smoking cessation is influenced by genetic variation in CYP2A6, coding for CYP2A6 which inactivates nicotine to cotinine, and metabolizes cotinine to 3′hydroxycotinine[3,4]. Sex, ancestry, and potentially mentholated cigarette smoking can alter CYP2A6 activity and the NMR. An increased understanding of the genetics of the NMR, and if they differ by sex and ancestry, will enhance application in oncology and in epidemiologic studies of disease risk where non- and former-smokers are included. The vast majority of genome-wide significant (GWS) variants found in genome-wide association studies (GWASs) of the NMR in smokers were found in the CYP2A6 region of chromosome 1924–28; these GWASs all controlled for sex. Our primary aim was to identify sex differences in the genetic influences on CYP2A6 activity, measured by the NMR, and contrast these differences between AA and EA smokers. We performed sex-stratified GWASs of the NMR separately in EA and AA smokers
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