Effectiveness of nicotine patches in relation to genotype in women versus men: randomised controlled trial

Abstract

The overall effectiveness of nicotine replacement therapy could be greater if the therapy were targeted at those most likely to respond. Variants of the dopamine D2 receptor (DRD2 32806 C/T) have been implicated in the initiation and maintenance of smoking, 1 2 and these variants may also be related to response to nicotine replacement therapy.3 Additionally, mechanisms of nicotine addiction may differ in men and women. 4 With this evidence in mind, we examined whether the response to nicotine replacement therapy is modified by sex and genotype. Participants, methods, and resultsA randomised controlled trial of nicotine patches in 1991-2 recruited 1686 heavy smokers ( ≥ 15 cigarettes a day).5 The participants wore patches for 12 weeks. Abstinence from smoking was confirmed at one week by expired carbon monoxide concentration ≤ 10 ppm, and at 12, 24, and 52 weeks by salivary cotinine concentration ≤ 20 ng/ml (89% of cases) or by expired carbon monoxide concentration ≤ 10 ppm.In 1999-2000, we contacted 1532 of the 1625 participants still alive; the mean time from trial to follow up was 8.3 years. In all, 752/1532 (49%) gave a blood sample from which DRD2 32806 was successfully typed. Reported abstinence at follow up was confirmed by plasma cotinine concentration ≤ 20 ng/ml. Throughout, non-respondents were assumed to be smoking.Participants were older than non-participants (mean age at entry to trial, 43.0 years v 41.5 years; P = 0.002), more likely to be female (59% (445/752) v 53% (410/780); P = 0.01), and more likely to have quit for a year in the trial (11% (82) v 4% (33), P < 0.0001); 744 (99%) reported their racial background as white.The variant T allele of the dopamine D2 receptor DRD2 32806 (CT or TT genotype) was found in 41% (183/445) of women and 41% of men (127/307). Within each sex, there was no difference between the genotype groups in age, number of cigarettes a day, or dependency score.We measured effectiveness of the patches by the relative odds of abstinence for active and placebo patches over five cumulative time periods: one week, 12 weeks, 24 weeks, 52 weeks, and to follow up. Treatment by genotype and sex, and their interaction, was examined in a full logistic regression model. The three way interaction by genotype by sex was significant for all time periods (P = 0.009, P = 0.03, P = 0.006, P = 0.006, P = 0.004 respectively), and we therefore analysed the data for men and women separately.In women, the effectiveness of the patches differed with genotype at all time points (table). In men the genotype groups did not differ significantly at any time. In men with CC genotype an apparent trend in effectiveness was in an implausible direction, the patches being most effective long after therapy had stopped. In both sexes, when active and placebo groups were combined, the quit rate was not related to genotype. CommentIn women the effectiveness of nicotine patches seems to be related to genotype. Women with the variant T allele of the dopamine D2 receptor DRD2 32806 showed considerable benefit from...

Overview of the pharmacogenomics of cigarette smoking

“…211 Subsequent analyses of this cohort found the TaqI A1 allele was associated with higher abstinence rates in women but not men at all time points examined (EOT, 12, 24 and 52 months, 8 years). 212 Conversely, women with the TaqI A1 genotypes appear to do worse on bupropion, reporting more side effects and relapse at 12 months follow-up. 213,214 There is evidence the À141C Ins/Del variant in DRD2, which has been associated with increased transcriptional activity in vitro, 215 is predictive of outcomes to NRT or bupropion.…”

Association of the DRD2 gene Taq1A polymorphism and smoking behavior: A meta-analysis and new data

“…therapy (NRT) Lerman et al, 2006 ;Yudkin et al, 2004 ), whereas increased-function alleles (e.g., Taq1A2) have been reported to predict better response to bupropion ( David et al, 2007 ;Lerman et al, 2006 ;Swan et al, 2005 ). Nevertheless, some studies have failed to demonstrate an effect of DRD2 genotype on smoking cessation ( Berlin, Covey, Jiang, & Hamer, 2005 ).…”

Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: New data from the Patch in Practice trial and pooled analyses

“…The duration of treatment with active nicotine (N= 341) and placebo patches (N= 340) was 12 weeks. Details regarding the Patch II trial (Imperial Cancer Research Fund General Practice Research Group, 1993, and the 8-year follow-up (Patch II study) have been comprehensively described elsewhere Yudkin et al, 2003Yudkin et al, , 2004. The mean age of participants was 42 years 11 months (S.D.…”