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 results
A 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 ν 41.5 years; P = 0.002), more likely to be female (59% (445/752) ν 53% (410/780); P = 0.01), and more likely to have quit for a year in the trial (11% (82) ν 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.
Table 1.
Biochemically confirmed abstinence from smoking by sex and DRD2 32806 genotype
|
Difference in odds ratios (P value)
|
||||||
|---|---|---|---|---|---|---|
| Period of abstinence | Genotype | Active patch (No (%)) | Placebo patch (No (%)) | Odds ratio (95% confidence interval) | Before adjustment | After adjustment* |
| Women | ||||||
| 1 week | CT or TT | 42/93 (45) | 13/90 (14) | 4.9 (2.4 to 10.0) | 0.001 | 0.001 |
| CC | 33/125 (26) | 34/137 (25) | 1.1 (0.6 to 1.9) | |||
| 12 weeks | CT or TT | 21/93 (23) | 6/90 (7) | 4.1 (1.6 to 10.7) | 0.03 | 0.02 |
| CC | 16/125 (13) | 17/137 (12) | 1.0 (0.5 to 2.2) | |||
| 24 weeks | CT or TT | 17/93 (18) | 5/90 (6) | 3.8 (1.3 to 10.8) | 0.03 | 0.02 |
| CC | 12/125 (10) | 15/137 (11) | 0.9 (0.4 to 1.9) | |||
| 52 weeks | CT or TT | 14/93 (15) | 5/90 (6) | 3.0 (1.0 to 8.7) | 0.04 | 0.02 |
| CC | 10/125 (8) | 15/137 (11) | 0.7 (0.3 to 1.6) | |||
| 8 years | CT or TT | 11/93 (12) | 4/90 (4) | 2.9 (0.9 to 9.4) | 0.02 | 0.01 |
| CC | 6/125 (5) | 13/137 (9) | 0.5 (0.2 to 1.3) | |||
| Men | ||||||
| 1 week | CT or TT | 27/67 (40) | 19/60 (32) | 1.5 (0.7 to 3.0) | 0.59 | 0.58 |
| CC | 40/91 (44) | 26/89 (29) | 1.9 (1.0 to 3.5) | |||
| 12 weeks | CT or TT | 17/67 (25) | 11/60 (18) | 1.5 (0.6 to 3.6) | 0.46 | 0.43 |
| CC | 21/91 (23) | 10/89 (11) | 2.4 (1.0 to 5.4) | |||
| 24 weeks | CT or TT | 11/67 (16) | 9/60 (15) | 1.1 (0.4 to 2.9) | 0.09 | 0.07 |
| CC | 17/91 (19) | 5/89 (6) | 3.9 (1.4 to 11.0) | |||
| 52 weeks | CT or TT | 9/67 (13) | 9/60 (15) | 0.9 (0.3 to 2.4) | 0.07 | 0.07 |
| CC | 15/91 (16) | 5/89 (6) | 3.3 (1.2 to 9.6) | |||
| 8 years | CT or TT | 7/67 (10) | 7/60 (12) | 0.9 (0.3 to 2.7) | 0.07 | 0.06 |
| CC | 12/91 (13) | 3/89 (3) | 4.4 (1.2 to 16.0) | |||
Periods of abstinence are cumulative, with repeated biochemical confirmation. For details see methods.
Adjustment for age, cigarettes per day, and dependency score before quit attempt.
Comment
In 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 patches, whereas those with the more common CC genotype did not. The increased effectiveness reflected a tendency to a higher quit rate with the active patches and a lower quit rate with placebo patches. No significant relation between genotype and patch effectiveness was seen for men.
Modelling showed that the response bias in favour of quitters and of women could not account for our results, as the bias affected the nicotine and placebo groups equally and so cancels out in the odds ratio for patch effectiveness. The results are also not explained by an association between genotype and success at quitting, as this could account for only a marginal difference in odds ratios between genotypes and would affect men and women similarly. We therefore hypothesise that nicotine replacement therapy works through different processes and is subject to different genetic influences in men and women.
This article was posted on bmj.com on 19 March 2004: http://bmj.com/cgi/doi/10.1136/bmj.38050.674826.AE
We thank Lesley Jones and Alice Fuller for computing help and John Stapleton for valuable comments and suggestions.
Contributors: RW, PY, and M Murphy wrote the protocol and obtained funding. M Munafò and PY devised and carried out the analysis. KH traced subjects and administered the study; SR and SW collected patient data and took blood samples. RW established laboratory procedures; EJ and SG carried out DNA extraction and genotyping. PY wrote the paper, with critical revision by all other authors. PY is the guarantor.
Funding: The study was supported by Cancer Research UK. The sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.
Competing interests: None declared.
Ethical approval: Ethical approval was obtained from the Anglia and Oxford Multicentre Research Ethics Committee, and from the 86 local research ethics committees covering the areas of residence of the patients.
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