Genetic Prediction of Smoking Cessation Medication Side Effects: A Genome-Wide Investigation of Abnormal Dreams on Varenicline.

Varenicline, the most efficacious smoking cessation monotherapy, produces abnormal dreams. Although genetic contributions to varenicline-associated nausea and cessation have been identified, the role of genetics in abnormal dreams is unknown. We conducted a genomewide association study (GWAS) of abnormal dreams in 188 European ancestry smokers treated with varenicline (NCT01314001). Additive genetic models examined the likelihood of experiencing abnormal dreams 2 weeks following varenicline initiation. For the top locus, we tested for selectivity to varenicline, effects on cessation, replication, and generalizability to African ancestry (AA) individuals. The top GWAS variant associated with abnormal dreams was rs901886, mapping to intron 2 of ICAM5 on chromosome 19. The prevalence of abnormal dreams in those with rs901886 CC, CT, and TT genotypes was 15%, 36%, and 62%, respectively (odds ratio = 2.94 for T vs. C, 95% confidence interval = 1.92-4.55, P = 2.03e-7; T allele frequency = 52%). This rs901886 association was selective to varenicline (P values > 0.05 on nicotine patch and placebo). There were also positive associations for rs901886 T (vs. C allele, P = 0.03) and for abnormal dreams (P = 0.06) with varenicline-aided cessation. Neither rs901886 (P = 0.40) nor abnormal dreams (P = 0.24) were associated with adherence. A similar direction of effect of rs901886 on abnormal dreams was observed in a second varenicline trial (NCT01836276). In AA individuals (n = 137), rs901886 was not associated with abnormal dreams (P = 0.41), but there was an association for a variant located ~ 74.4 kb 5' of ICAM5 (P = 2.56e-3). Variation in ICAM5 may influence abnormal dreams and cessation on varenicline. These findings provide additional support for genetically optimized smoking cessation approaches.

Does sex alter the relationship between CYP2B6 variation, hydroxybupropion concentration and bupropion-aided smoking cessation in African Americans? A moderated mediation analysis.

BACKGROUND AND AIMS: CYP2B6, a genetically variable enzyme, converts bupropion to its active metabolite hydroxybupropion. CYP2B6 activity and bupropion-aided cessation differ between women and men. The aim of this study was to determine whether genetically normal (versus reduced) CYP2B6 activity increases bupropion-aided cessation in African American smokers via higher hydroxybupropion concentration, and whether this differs by sex. DESIGN AND SETTING: Secondary analysis of a smoking cessation clinical trial (NCT00666978). PARTICIPANTS/CASES: African American light smokers (≤ 10 cigarettes/day). INTERVENTIONS: Participants were treated with bupropion for 7 weeks. MEASUREMENTS: Participants with detectable bupropion and/or hydroxybupropion concentrations were divided into normal (n = 64) and reduced (n = 109) CYP2B6 activity groups based on the presence of decreased-function CYP2B6*6 and CYP2B6*18 alleles. Biochemically verified smoking cessation was assessed at week 3, end of treatment (7 weeks) and follow-up (26 weeks). FINDINGS: Normal (versus reduced) CYP2B6 activity was associated with increased cessation at week 7, which was mediated by higher hydroxybupropion concentration [odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.03, 1.78]; this mediation effect persisted at week 26 (OR = 1.23, 95% CI = 1.02, 1.70). The mediation effect was similar in women (n = 116; OR = 1.33, 95% CI = 1.01, 2.30) and men (n = 57; OR = 1.33, 95% CI = 0.92, 3.87). Moreover, sex did not appear to moderate the mediation effect, although this should be tested in a larger sample. CONCLUSIONS: In African American light smokers with verified early bupropion use, genetically normal CYP2B6 activity appears to be indirectly associated with greater smoking cessation success in a relationship mediated by higher hydroxybupropion concentration. The mediating effect of higher hydroxybupropion concentration on smoking cessation persists beyond the active treatment phase and does not appear to differ by sex.

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

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.

Social determinants of alcohol and cigarette use by race/ethnicity: Can we ignore measurement issues?

Psychometric critiques of cross-cultural research emphasize testing whether instruments measure the same construct across cultural groups. We tested for measurement invariance (by race/ethnicity) of instruments used to evaluate the relationship between alcohol and tobacco use with perceived discrimination and socioeconomic status (SES). Tests of psychometric equivalence across race/ethnicity focused on: the latent organization of constructs (configural invariance); if observed indicators have equal factor loadings or "true score" variance (metric invariance); and whether manifest indicators change uniformly contingent on change in the latent variable (scalar invariance). A cross-sectional survey of 2,376 cigarette smokers (794 Black, 786 Latinx, 796 White; mean age = 43 [SD = 12]; 58% female) was recruited via an online research panel. Discrimination was indicated by self-report; SES was indicated by self-reported education, employment, income, and the "SES Ladder;" alcohol use was indicated by frequency and typical quantity of drinking, and frequency of heavy drinking; tobacco use was indicated by frequency of smoking, cigarettes per smoking day, and time to first cigarette. All instruments demonstrated configural invariance; either full metric invariance (alcohol and discrimination) or partial metric invariance (tobacco and SES); and all constructs demonstrated partial scalar invariance. Results support psychometric critiques; for example, all of the SES indicators violated assumptions of classical measurement theory for valid between group comparisons. All of our instruments displayed some degree of systematic bias in measurement across race/ethnicity. Studies testing ethnic/racial differences may need to move beyond classical measurement theory, and may benefit from using statistical approaches that can test for (and model) bias in measurement. (PsycInfo Database Record (c) 2020 APA, all rights reserved).