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Efficacy of genotype notification to Japanese smokers on smoking cessation—An intervention study at workplace
Cancer Epidemiology 34 (2010) 96–100
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Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Efficacy of genotype notification to Japanese smokers on smoking cessation—An intervention study at workplace§ Asahi Hishida a,*, Tetsuro Terazawa b, Toshiko Mamiya b, Hidemi Ito c, Keitaro Matsuo c, Kazuo Tajima c, Nobuyuki Hamajima a a Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8550, Japan b The Bank of Tokyo-Mitsubishi UFJ (former Tokai Bank), Nagoya, Japan c Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 26 November 2009
Objectives: It is well-known that smoking causes many diseases including cancers. Informing smokers of their genotypes associated with the vulnerability to the harms of smoking may be effective measures for smoking cessation. The present study examined the effects of genotype notification of an oncogene (Lmyc) genotype to smokers on their behavior to quit smoking. Methods: Subjects were 562 employees of a bank who answered to be a smoker for a questionnaire used at annual health checkup at workplace from July to December 2002. Those enrolled on August, October, and December were allocated into the genotype notification group (intervention group), and the rest into the controls. Among 286 smokers allocated into the intervention group, 257 participants (89.9%) agreed to genotype testing. One year after the enrollment, a follow-up questionnaire survey was conducted for all smokers including controls. Results: Those who stated to have quitted smoking were 22 (8.0%) among the 276 controls and 15 (5.8%) among the 257 genotype notified participants, providing that the odds ratio (OR) of cessation for the intervention was 0.64 (95% confidence interval, 0.32–1.28). No psychological problems associated with genotype notification were observed. Conclusion: The present study did not show positive effects of genotype notification on smoking cessation rate. To elevate the cessation rate, methods to explain and notify genotypes should be improved. ß 2009 Elsevier Ltd. All rights reserved.
Keywords: Genotype notification L-myc genotype Smoking cessation
1. Introduction Smoking is well known as a leading cause of many diseases. Globally, an 85% of male lung cancer and 47% of female lung cancer was estimated to be attributable to tobacco smoking [1]. Cigarette smoking is also a primary cause of deaths from other human cancers [2–5], coronary heart disease, chronic pulmonary disease and stroke [6]. In addition to educating smokers about the harmfulness of tobacco smoking, informing smokers of their genotypes associated with the vulnerability to the harms of smoking might be effective measures to induce them to quit smoking. The effects were hypothesized due to the recognition of disease risk as well as health consciousness elevated with genotype testing. According to
§ This work was performed at the Bank of Tokyo-Mitsubishi UFJ (former Tokai Bank) and Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. AH was a former resident, and NH were former staffs of Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. * Corresponding author. Tel.: +81 0 52 744 2132; fax: +81 0 52 744 2971. E-mail address: [email protected] (A. Hishida).
1877-7821/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2009.11.008
Health Belief Model, behavior change (e.g. smoking cessation) is dependent on the people’s recognition of themselves to be at risk of severe health consequences resulting from their behavior (e.g. they believe that smoking damages their health) [7]. As explained in Expanded Parallel-Process Model, the more people believe they are susceptible to a serious threat (e.g. high perceived risk or harboring high risk genotype), the more they are motivated to initial the evaluation of the recommended response (e.g. smoking cessation) [8,9]. To date, there are a few randomized intervention studies to examine the efficacy of genotype notification. A study in the United States evaluated the long-term impact of genetic susceptibility biomarker (CYP2D6 genotype) feedback on smoking behavior change, resulting that the genetic susceptibility feedback did not improve the cessation rate [10,11]. Another study reported that smokers notified to have GSTM1 genotype had a high cessation rate compared with the control group [12]. Since telephone counseling was provided only for the notified group, the contribution of genotype notification to the higher cessation rate was undetermined. A study in the United Kingdom to examine the psychological impact of GSTM1 genotype testing for smokers were
A. Hishida et al. / Cancer Epidemiology 34 (2010) 96–100
found that those with GSTM1 null type had greater motivation to quit smoking, and that the depression among the genotype notified group was significantly low one week after the notification and not different two months after [13]. In Japan, there were also several reports evaluating the efficacy of genotype notification on smoking cessation [14–17]. In those studies, genotypes of the genes possibly modifying smokingrelated disease risks, L-myc, GSTM1, GSTT1, NQO1, and CYP1A1, were applied. In our previous studies, smoking elevated markedly the risk of lung cancer among those with L-myc SS (odds ratio, OR = 3.19; 95% CI 0.92–11.06) and LS (OR = 2.30; 95% CI 1.05–5.04) genotypes relative to among those with LL genotype (OR = 0.92; 95% CI 0.32–2.68) [18], and for the risk of esophageal cancer, OR = 7.57 (95% CI 1.91–30.03), 6.40 (2.74–14.95), and 1.77 (0.54– 5.75), respectively [19]. This L-myc polymorphism is also reported to affect the prognosis of lung cancer [20,21]. The L-myc polymorphism examined here is a T to A variation located in the second intron of the L-myc gene that produces short (S) and long (L) fragments after digestion by EcoRI, the precise biological influence of which is not yet fully clarified [20,21]. Among those studies, one at a cancer hospital showed a significantly higher cessation rate in 100 female smokers notified of L-myc genotype (p = 0.024), but not in 145 male smokers, compared with the controls (119 female smokers and 130 male smokers). The insignificant result among the males could be due to the limited effect or due to the small statistical power. This study aimed to reexamine the effects of L-myc genotype notification to smokers on their smoking behavior in a male-dominant workplace with larger number of male subjects, and also to re-evaluate the efficacy of genotype notification on smoking behaviors, which is currently still under controversy worldwide. The participants were enrolled at an annual health checkup, although the situation differed from the previous study whose participants were first-visit outpatients. 2. Materials and methods 2.1. Design and participants Subjects were employees of a bank, who answered to be a smoker for a questionnaire used at annual health checkup at workplace from July to December in 2002. Informed consent of genotype notification was obtained individually from each smoker after handing the participants a booklet named ‘‘Smoking and genetic polymorphism: what is the genetic traits to cause tobaccorelated diseases. Hi smokers! Can your genes bear tobacco?’’. The booklet was made of eight colored pages including information on tobacco-related diseases, genetic polymorphisms in general, concept of tobacco carcinogen susceptible genotypes, CYP1A1, GSTM1, L-myc, relative risk of L-Myc genotype for esophageal cancer (the results derived from [16]), genotypes associated with nicotine dependence, damages caused by smoking, and benefits of smoking cessation. The information given about the L-myc genotype in this booklet is as follows: L-myc gene has a missense G/T polymorphism at nucleotide position 2886, G/G, G/T and T/T genotype of which is called LL, LS and SS genotype, respectively. Our case–control study at Aichi Cancer Center revealed that the OR of esophageal cancer for smoking was 7.57 in SS, 6.40 in LS and 1.77 in LL, respectively. In three months (August, October and December in 2002), 257 participants (89.9%) among 286 smokers invited (‘‘intervention group’’) agreed to genotype testing. Blood samples were numbered in a manner corresponding to the questionnaire, but the name of participants was not attached to the tubes of the blood sample. The health staff recorded the number for each participant. In the other three months (July, September and November in 2002), all 276 smokers agreed to be followed up as a control group.
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Three months after the enrollment, genotype reports were sent in sealed envelopes to the section of health management. In the reports, the explanation was attached that smoking elevates the risk of esophageal cancer substantially among those with SS (OR = 8) and LS (OR = 7), while OR = 2 among those with LL genotype, and similar for lung cancer. Additionally, the explanation that there are many genotypes associated with the susceptibility of smoking was provided. The staff (public nurses) handed the report to each participant without opening the envelope according to the number specified on the envelope. They added general comments on the genotype for each participant, and provide specific comments when participants asked the details. Strong messages to quit smoking were not included their explanation. 2.2. Questionnaire At enrollment, a questionnaire to ask the stage of change was distributed to all the participants. One year after the enrollment, a follow-up questionnaire about the stage of change was conducted for all participants. The questionnaires at enrollment, just before genotype notification, and at the follow-up one year after the enrollment were anonymized, and sent to the study office at Aichi Cancer Center. The questionnaires were linked with the number put on each questionnaire. The stage of change concerning smoking cessation was classified into four categories; no concern, feel concern but have no intention to quit smoking, have an intention to quit smoking but not in one month, and wish to quit smoking within one month. The second and third categories were combined into ‘‘no intention to quit’’ in the analysis. The ‘‘no concern’’, ‘‘no intention’’, and ‘‘wish to quit’’ correspond to the category, ‘‘precontemplation’’, ‘‘contemplation’’, and ‘‘preparation’’, respectively, by Prochaska et al. [22]. At the follow-up, the response to genotype notification was evaluated by the following question, ‘‘how did you feel when your genotypes were notified?’’ The response was classified as (1) relieved, (2) anxious, (3) neither, and (4) cannot remember the genotypes or ‘‘forgot’’ how they felt. 2.3. Genotyping A L-myc polymorphism was genotyped by a PCR with confronting two-pair primers [23]. The genotype frequency of Lmyc for 257 blood available smokers was in Hardy-Weinberg equilibrium (61 for LL genotype, 126 for LS genotype, and 70 for SS genotype, x2 = 0.086, p = 0.770). 2.4. Statistical methods Cessation rates and stage of change of two groups were tested by a two-side Fisher’s exact test. Logistic regression analysis was performed for estimating odds ratios (ORs) and 95% confidence intervals (CIs). Age adjustment in the logistic analysis was done as a continuous variable. Statistical analysis was conducted with STATA version 7 (STATA Corporation, College Station, TX). 2.5. Ethics This study was approved at Ethics Committee of Aichi Cancer Center. Individuals willing to participate in the study provided written informed consent for participation. 3. Results Table 1 shows sex and age distributions of the 562 participants (527 males and 35 females). In the intervention group, 89.9% (243 males and 14 females) agreed the genotype testing. There were no
A. Hishida et al. / Cancer Epidemiology 34 (2010) 96–100
98 Table 1 Sex, age distribution and stage of the subjects. Intervention group a
Control group
Total
N = 286
(%)
N = 276
(%)
Males Females
270 16
(94.4) (5.6)
257 19
(93.1) (6.9)
54 94 99 35 4
(18.9) (32.9) (34.6) (12.2) (1.4)
61 90 65 58 2
(22.1) (32.6) (23.6) (21.0) (0.7)
58 210 17 1
(20.3) (73.4) (5.9) (0.3)
47 219 9 1
(17.0) (79.3) (3.3) (0.4)
Age
20–29 30–39 40–49 50–60 60–
Stage No concern No intention Wish to quit No answer
a Twenty-nine smokers (27 males and 2 females) who did not agree the genotyping test are included.
Table 3 shows the cessation rate according to the L-myc genotype and the responses to genotype testing. Cessation rates did not differ significantly according to L-myc genotype (5.6% in LS and 7.1% in SS, compared with 4.9% in LL; p = 1.000 and p = 0.723, respectively). As for the responses to genotype notification, those who felt ‘‘anxious’’ after notification showed an insignificantly higher cessation rate than those who felt ‘‘relieved’’ after notification (6.7% in ‘‘anxious’’ and 3.6% in ‘‘relieved’’; p = 1.000). Those who stated ‘‘relieved’’ was 41.0% in LL, 2.4% in LS, and 0.0% in SS; the percentage for LL was significantly higher than that for LS or SS (p < 0.001 and p < 0.001, respectively). Those who stated ‘‘anxious’’ was 11.5% in LL, 31.0% in LS, and 41.4% in SS; the percentage for LS or SS was significantly higher than that for LL (p = 0.004 and p < 0.001, respectively). There were no claims or consultations on genotype to the health management section, and serious responses of the genotype-notified participants were not observed throughout the study. 4. Discussion
Table 2 Quitting behavior and stage of change at one year after genotype notification. Notified group N = 257 Quit Not quit No concern No intention Wish to quit No answer No response
Control group (%)
15
N = 276
(5.8)
203 26 162 15 0 39
22
(79.0) (10.7) (66.9) (6.2) (0.0) (16.1)
223 30 176 16 1 31
(%) (8.0) (80.8) (10.9) (63.8) (6.0) (0.4) (11.2)
differences in sex and age distributions between those who agreed and those who refused. Table 2 shows the stage of smokers at one year after the enrollment. Those who stated to have quitted smoking were 22 (8.0%) among the 276 controls and 15 (5.8%) among the 257 genotype notified participants. The difference in the cessation rate between the two groups was not significant (p = 0.395). When 29 smokers who refused genotype tests were regarded as non-quitters, the cessation rate of whole intervention group was 5.2% (p = 0.234 in comparison with the rate among the controls). The OR of cessation for the intervention adjusted by age, sex and stage at enrollment was not statistically significant (OR = 0.64, 95% CI 0.32–1.28, p = 0.209). Among non-quitters, the difference in the stage of smokers at one year after enrollment between the two groups was not significant (x2 = 0.961 d.f. = 3, p = 0.811). In both groups, the subjects in the stage of ‘‘wish to quit’’ (11.8% in the intervention group and 11.1% in the controls) tended to have a high cessation rate compared with ‘‘no concern’’ (0.0% and 4.3%, respectively) or ‘‘no intention’’ (6.2% and 8.2%) group, although statistically not significant.
This study based on the questionnaire found that the cessation rate was 5.8% among the genotype notified participants, and 8.0% in the controls. The rate was not significantly different according to the L-myc genotype. There were no such severe substantial psychological/social problems as to require counseling relating with the genotype notification, although the percentage who stated to ‘‘relieved’’ was significantly low among those with LS or SS relative to those with LL, and that of ‘‘anxious’’ was significantly higher among those with LS or SS relative to those with LL. The genotype frequency of L-myc was 23.7% for LL, 49.0% for LS, and 27.2% for SS among the 257 genotyped participants. The distribution was similar to the other studies in Japanese, for example, 24.5%, 55.6%, and 19.9%, respectively, among 241 noncancer controls [18]. Generally, the cessation rate among health checkup examinees is relatively low; a follow-up study conducted in 1997–1998 reported that one-year cessation rate was 6.0% among 2190 health checkup examinees [24]. Cessation rate was reportedly higher in patients than in healthy individuals, which might be attributable to the high consciousness of the harms of smoking among the patients [25]. In the present study, the controls showed a slightly higher cessation rate (8.0%), possibly because situations surrounding the workplaces were changing against smoking. On August 2 in 2002, Health Promotion Act was issued in Japan, which defines the responsibility of owners/managers to prevent passive smoking at their facilities. Accordingly, the company might be influenced by the Act; a part of smokers might realize that smoking was disadvantageous not only for their health but also for his/her promotion or evaluation at workplace. The reasons for no effects of genotype notification were not clear. It was possible that they had no time to understand the implication of genotype testing and to
Table 3 Cessation rate in the percentage according to L-myc genotype and response of the notified group to the question ‘‘How did you feel when your genotypes were notified?’’. Response
L-myc genotype
Total
LL
LS
N
%
Relieved Anxious Neither Forgot Others No answer/No response
25 7 15 5 3 6
4.0 0.0 6.7 20.0 0.0 0.0
Total
61
4.9
N: number of the notified subjects.
N
SS %
N
%
N
%
3 39 39 17 2 26
0.0 7.7 0.0 11.8 0.0 7.7
0 29 15 14 1 11
0.0 6.9 6.7 14.3 0.0 0.0
28 75 69 36 6 43
3.6 6.7 2.9 13.9 0.0 4.7
126
5.6
70
7.1
257
5.8
A. Hishida et al. / Cancer Epidemiology 34 (2010) 96–100
consider the messages from the results. Lack of the knowledge concerning genotype tests might have diminished the effects of the intervention on smoking behavior. In addition, the bank was in the midst of restructuring, so that the majority might have been nervous or under stress, which could have additionally diluted the effects of genotype notification. In this study, the difference in the cessation rate was not significant among those with the different stage of smokers at enrollment possibly due to the limited number of subjects, although the smokers who ‘‘wished to quit’’ showed a trend of a higher cessation rate compared with ‘‘no concern’’ or ‘‘no intention’’ group. The tendency in the intervention group was similar to that in the controls. In the previous reports, the stage of change was a good predictor of smoking cessation [26,27]. The cessation rate according to L-myc genotype revealed no statistically significant difference in this study, however, there still seems to be a possibility that genotype notification could be more effective in those with risky genotypes, and further investigation with larger number of study subjects are required to verify this hypothesis. Although those who stated ‘‘relieved’’ after the notification was more in LL genotype, such response was not strongly related to the cessation rate; 3.6% for ‘‘relieved’’ and 6.7% for ‘‘anxious’’. The high uptake rate (89.9%) of genotype testing might be explained by the fact that this study was conducted in one bank and the workers are cooperative to the research, and another plausible reason may be the regional characteristics of Nagoya citizens who tend to unite and be faithful to authorities like Nagoya University Graduate School of Medicine. There could also be potential harm associated with genotype notification. In this study, any serious problems were not observed. To date, several reports about genotype notification to smokers were made, few of which ever documented such severe problems [10–17], although some reports pointed out that receiving information about own disease risk can be potentially anxiety provoking [28–30]. The response to polymorphism genotype tests might differ from genotype notification of hereditary diseases like BRCA1/BRCA2 mutations in breast cancer [31,32] and cystic fibrosis [33]. A study reported that genotype disclosure to hereditary nonpolyposis colorectal cancer carriers did not demonstrate significant adverse psychological outcomes [34]. In this study, there was no request from the participants to provide genetic counseling or other psychological support, suggesting that the anxieties related to genotype notification were not so severe even in those with the high-risk genotypes. Nevertheless, it will be wise to be careful about the response of the participants after genotype notification. There were several limitations in this study. First, the cessation was not confirmed by a biological test, such as carbon mono-oxide in the breath and nicotine/cotinine concentration in urine. Second, the changes in perception of their disease risk after the genotype notification were not precisely measured, but we evaluated only the association with the final outcome, the stage of change. In this study we also used our original criteria for the stage of change to be suitable for practical application, which should have been replaced with more faithful outcome measures to the original definition by Prochaska et al. [22], although it would be even better if replaced with more recent criteria of transtheoretical model consisting of four constructs: stage of change, decisional balance, self-efficacy, and process of change [35,36]. Third, the emotional burden derived from the genotype notification was not measured with an established questionnaire. In addition, indicators of socioeconomic status like income levels, educational levels, or job title/level were not available in this study mainly in consideration of privacy of the participants. In this study, only the association between genotype notification and its effect on smoking cessation is studied, it would have been better if the effects of genotype notification on more
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detailed behavioral changes such as changes in stages of change were evaluated, and some other factors that can influence smoking cessation rate like age or gender should also have been included in the analyses. The sample size in this study is small, and the number of those with an elevated risk for disease is even smaller, making the possibility to analyze the effect of genotype notification to this high-risk group very limited. Based on these limitations, the findings had to be carefully interpreted. There might be some other factors related to smoking cessation. Nicotine dependence and genetic traits of addiction such as genotypes of dopamine reward pathways were also reported to influence smoking behaviors of the individuals [37,38]. Diagnosis and severity of disease was reported to influence the cessation rate [25,39]. To promote smoking cessation more effectively, it would be necessary to take these factors into consideration. In conclusion, the present study based on the self-administered questionnaire did not show positive effects of genotype notification on smoking cessation. To elevate the cessation rate, methods to explain and notify genotypes should be improved. Furthermore, the combinations to other methods including nicotine replacement therapy needed to be explored. Conflict of interests The authors have no conflict of interests to declare. Acknowledgments This study was supported in part by a Grant-in-Aid for Cancer Research from the Japanese Ministry of Health, Labour and Welfare. References [1] Ebbert JO, Sood A, Hays JT, Dale LC, Hurt RD. Treating tobacco dependence: review of the best and latest treatment options. J Thorac Oncol 2007;2:249–56. [2] Nishino Y, Inoue M, Tsuji I, Wakai K, Nagata C, Mizoue T, et al. Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan. Tobacco smoking and gastric cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol 2006;36:800–7. [3] Nagata C, Mizoue T, Tanaka K, Tsuji I, Wakai K, Inoue M, et al. Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan. Tobacco smoking and breast cancer risk: an evaluation based on a systematic review of epidemiological evidence among the Japanese population. Jpn J Clin Oncol 2006;36:387–94. [4] Eguchi H, Nakachi K. Smoking as a risk factor for pancreatic cancer. Nippon Rinsho 2006;64(Suppl 1):10–3 (in Japanese). [5] Mizoue T, Inoue M, Tanaka K, Tsuji I, Wakai K, Nagata C, et al. Research Group for the Development, Evaluation of Cancer Prevention Strategies in Japan. Tobacco smoking and colorectal cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol 2006;36:25–39. [6] Morgan GD, Backinger CL, Leischow SJ. The future of tobacco-control research. Cancer Epidemiol Biomarkers Prev 2007;16:1077–80. [7] Janz NK, Becker MH. The Health Belief Model: a decade later. Health Educ Q 1984;11:1–47. [8] Witte K. Putting the fear back into fear appeals: the extended parallel process model. Comm Mono 1992;59:329–49. [9] Etchegary H, Perrier C. Information processing in the context of genetic risk: implications for genetic-risk communication. J Genet Couns 2007;16:419– 32. [10] Audrain J, Boyd NR, Roth J, Main D, Caporaso NF, Lerman C. Genetic susceptibility testing in smoking-cessation treatment: one-year outcomes of a randomized trial. Addict Behav 1997;22:741–51. [11] Lerman C, Gold K, Audrain J, Lin TH, Boyd NR, Orleans CT, et al. Incorporating biomarkers of exposure and genetic susceptibility into smoking cessation treatment: effects on smoking-related cognitions, emotions, and behavior change. Health Psychol 1997;16:87–99. [12] McBride CM, Bepler G, Lipkus IM, Lyna P, Samsa G, Albright J, et al. Incorporating genetic susceptibility feedback into a smoking cessation program for African-American smokers with low income. Cancer Epidemiol Biomarkers Prev 2002;11:521–8. [13] Sanderson SC, Humphries SE, Hubbart C, Hughes E, Jarvis MJ, Wardle J. Psycological and behavioural impact of genetic testing smokers for lung cancer risk: a phase II exploratory trial. J Health Psychol 2008;13:481–94.
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Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Efficacy of genotype notification to Japanese smokers on smoking cessation—An intervention study at workplace§ Asahi Hishida a,*, Tetsuro Terazawa b, Toshiko Mamiya b, Hidemi Ito c, Keitaro Matsuo c, Kazuo Tajima c, Nobuyuki Hamajima a a Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8550, Japan b The Bank of Tokyo-Mitsubishi UFJ (former Tokai Bank), Nagoya, Japan c Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 26 November 2009
Objectives: It is well-known that smoking causes many diseases including cancers. Informing smokers of their genotypes associated with the vulnerability to the harms of smoking may be effective measures for smoking cessation. The present study examined the effects of genotype notification of an oncogene (Lmyc) genotype to smokers on their behavior to quit smoking. Methods: Subjects were 562 employees of a bank who answered to be a smoker for a questionnaire used at annual health checkup at workplace from July to December 2002. Those enrolled on August, October, and December were allocated into the genotype notification group (intervention group), and the rest into the controls. Among 286 smokers allocated into the intervention group, 257 participants (89.9%) agreed to genotype testing. One year after the enrollment, a follow-up questionnaire survey was conducted for all smokers including controls. Results: Those who stated to have quitted smoking were 22 (8.0%) among the 276 controls and 15 (5.8%) among the 257 genotype notified participants, providing that the odds ratio (OR) of cessation for the intervention was 0.64 (95% confidence interval, 0.32–1.28). No psychological problems associated with genotype notification were observed. Conclusion: The present study did not show positive effects of genotype notification on smoking cessation rate. To elevate the cessation rate, methods to explain and notify genotypes should be improved. ß 2009 Elsevier Ltd. All rights reserved.
Keywords: Genotype notification L-myc genotype Smoking cessation
1. Introduction Smoking is well known as a leading cause of many diseases. Globally, an 85% of male lung cancer and 47% of female lung cancer was estimated to be attributable to tobacco smoking [1]. Cigarette smoking is also a primary cause of deaths from other human cancers [2–5], coronary heart disease, chronic pulmonary disease and stroke [6]. In addition to educating smokers about the harmfulness of tobacco smoking, informing smokers of their genotypes associated with the vulnerability to the harms of smoking might be effective measures to induce them to quit smoking. The effects were hypothesized due to the recognition of disease risk as well as health consciousness elevated with genotype testing. According to
§ This work was performed at the Bank of Tokyo-Mitsubishi UFJ (former Tokai Bank) and Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. AH was a former resident, and NH were former staffs of Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. * Corresponding author. Tel.: +81 0 52 744 2132; fax: +81 0 52 744 2971. E-mail address: [email protected] (A. Hishida).
1877-7821/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2009.11.008
Health Belief Model, behavior change (e.g. smoking cessation) is dependent on the people’s recognition of themselves to be at risk of severe health consequences resulting from their behavior (e.g. they believe that smoking damages their health) [7]. As explained in Expanded Parallel-Process Model, the more people believe they are susceptible to a serious threat (e.g. high perceived risk or harboring high risk genotype), the more they are motivated to initial the evaluation of the recommended response (e.g. smoking cessation) [8,9]. To date, there are a few randomized intervention studies to examine the efficacy of genotype notification. A study in the United States evaluated the long-term impact of genetic susceptibility biomarker (CYP2D6 genotype) feedback on smoking behavior change, resulting that the genetic susceptibility feedback did not improve the cessation rate [10,11]. Another study reported that smokers notified to have GSTM1 genotype had a high cessation rate compared with the control group [12]. Since telephone counseling was provided only for the notified group, the contribution of genotype notification to the higher cessation rate was undetermined. A study in the United Kingdom to examine the psychological impact of GSTM1 genotype testing for smokers were
A. Hishida et al. / Cancer Epidemiology 34 (2010) 96–100
found that those with GSTM1 null type had greater motivation to quit smoking, and that the depression among the genotype notified group was significantly low one week after the notification and not different two months after [13]. In Japan, there were also several reports evaluating the efficacy of genotype notification on smoking cessation [14–17]. In those studies, genotypes of the genes possibly modifying smokingrelated disease risks, L-myc, GSTM1, GSTT1, NQO1, and CYP1A1, were applied. In our previous studies, smoking elevated markedly the risk of lung cancer among those with L-myc SS (odds ratio, OR = 3.19; 95% CI 0.92–11.06) and LS (OR = 2.30; 95% CI 1.05–5.04) genotypes relative to among those with LL genotype (OR = 0.92; 95% CI 0.32–2.68) [18], and for the risk of esophageal cancer, OR = 7.57 (95% CI 1.91–30.03), 6.40 (2.74–14.95), and 1.77 (0.54– 5.75), respectively [19]. This L-myc polymorphism is also reported to affect the prognosis of lung cancer [20,21]. The L-myc polymorphism examined here is a T to A variation located in the second intron of the L-myc gene that produces short (S) and long (L) fragments after digestion by EcoRI, the precise biological influence of which is not yet fully clarified [20,21]. Among those studies, one at a cancer hospital showed a significantly higher cessation rate in 100 female smokers notified of L-myc genotype (p = 0.024), but not in 145 male smokers, compared with the controls (119 female smokers and 130 male smokers). The insignificant result among the males could be due to the limited effect or due to the small statistical power. This study aimed to reexamine the effects of L-myc genotype notification to smokers on their smoking behavior in a male-dominant workplace with larger number of male subjects, and also to re-evaluate the efficacy of genotype notification on smoking behaviors, which is currently still under controversy worldwide. The participants were enrolled at an annual health checkup, although the situation differed from the previous study whose participants were first-visit outpatients. 2. Materials and methods 2.1. Design and participants Subjects were employees of a bank, who answered to be a smoker for a questionnaire used at annual health checkup at workplace from July to December in 2002. Informed consent of genotype notification was obtained individually from each smoker after handing the participants a booklet named ‘‘Smoking and genetic polymorphism: what is the genetic traits to cause tobaccorelated diseases. Hi smokers! Can your genes bear tobacco?’’. The booklet was made of eight colored pages including information on tobacco-related diseases, genetic polymorphisms in general, concept of tobacco carcinogen susceptible genotypes, CYP1A1, GSTM1, L-myc, relative risk of L-Myc genotype for esophageal cancer (the results derived from [16]), genotypes associated with nicotine dependence, damages caused by smoking, and benefits of smoking cessation. The information given about the L-myc genotype in this booklet is as follows: L-myc gene has a missense G/T polymorphism at nucleotide position 2886, G/G, G/T and T/T genotype of which is called LL, LS and SS genotype, respectively. Our case–control study at Aichi Cancer Center revealed that the OR of esophageal cancer for smoking was 7.57 in SS, 6.40 in LS and 1.77 in LL, respectively. In three months (August, October and December in 2002), 257 participants (89.9%) among 286 smokers invited (‘‘intervention group’’) agreed to genotype testing. Blood samples were numbered in a manner corresponding to the questionnaire, but the name of participants was not attached to the tubes of the blood sample. The health staff recorded the number for each participant. In the other three months (July, September and November in 2002), all 276 smokers agreed to be followed up as a control group.
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Three months after the enrollment, genotype reports were sent in sealed envelopes to the section of health management. In the reports, the explanation was attached that smoking elevates the risk of esophageal cancer substantially among those with SS (OR = 8) and LS (OR = 7), while OR = 2 among those with LL genotype, and similar for lung cancer. Additionally, the explanation that there are many genotypes associated with the susceptibility of smoking was provided. The staff (public nurses) handed the report to each participant without opening the envelope according to the number specified on the envelope. They added general comments on the genotype for each participant, and provide specific comments when participants asked the details. Strong messages to quit smoking were not included their explanation. 2.2. Questionnaire At enrollment, a questionnaire to ask the stage of change was distributed to all the participants. One year after the enrollment, a follow-up questionnaire about the stage of change was conducted for all participants. The questionnaires at enrollment, just before genotype notification, and at the follow-up one year after the enrollment were anonymized, and sent to the study office at Aichi Cancer Center. The questionnaires were linked with the number put on each questionnaire. The stage of change concerning smoking cessation was classified into four categories; no concern, feel concern but have no intention to quit smoking, have an intention to quit smoking but not in one month, and wish to quit smoking within one month. The second and third categories were combined into ‘‘no intention to quit’’ in the analysis. The ‘‘no concern’’, ‘‘no intention’’, and ‘‘wish to quit’’ correspond to the category, ‘‘precontemplation’’, ‘‘contemplation’’, and ‘‘preparation’’, respectively, by Prochaska et al. [22]. At the follow-up, the response to genotype notification was evaluated by the following question, ‘‘how did you feel when your genotypes were notified?’’ The response was classified as (1) relieved, (2) anxious, (3) neither, and (4) cannot remember the genotypes or ‘‘forgot’’ how they felt. 2.3. Genotyping A L-myc polymorphism was genotyped by a PCR with confronting two-pair primers [23]. The genotype frequency of Lmyc for 257 blood available smokers was in Hardy-Weinberg equilibrium (61 for LL genotype, 126 for LS genotype, and 70 for SS genotype, x2 = 0.086, p = 0.770). 2.4. Statistical methods Cessation rates and stage of change of two groups were tested by a two-side Fisher’s exact test. Logistic regression analysis was performed for estimating odds ratios (ORs) and 95% confidence intervals (CIs). Age adjustment in the logistic analysis was done as a continuous variable. Statistical analysis was conducted with STATA version 7 (STATA Corporation, College Station, TX). 2.5. Ethics This study was approved at Ethics Committee of Aichi Cancer Center. Individuals willing to participate in the study provided written informed consent for participation. 3. Results Table 1 shows sex and age distributions of the 562 participants (527 males and 35 females). In the intervention group, 89.9% (243 males and 14 females) agreed the genotype testing. There were no
A. Hishida et al. / Cancer Epidemiology 34 (2010) 96–100
98 Table 1 Sex, age distribution and stage of the subjects. Intervention group a
Control group
Total
N = 286
(%)
N = 276
(%)
Males Females
270 16
(94.4) (5.6)
257 19
(93.1) (6.9)
54 94 99 35 4
(18.9) (32.9) (34.6) (12.2) (1.4)
61 90 65 58 2
(22.1) (32.6) (23.6) (21.0) (0.7)
58 210 17 1
(20.3) (73.4) (5.9) (0.3)
47 219 9 1
(17.0) (79.3) (3.3) (0.4)
Age
20–29 30–39 40–49 50–60 60–
Stage No concern No intention Wish to quit No answer
a Twenty-nine smokers (27 males and 2 females) who did not agree the genotyping test are included.
Table 3 shows the cessation rate according to the L-myc genotype and the responses to genotype testing. Cessation rates did not differ significantly according to L-myc genotype (5.6% in LS and 7.1% in SS, compared with 4.9% in LL; p = 1.000 and p = 0.723, respectively). As for the responses to genotype notification, those who felt ‘‘anxious’’ after notification showed an insignificantly higher cessation rate than those who felt ‘‘relieved’’ after notification (6.7% in ‘‘anxious’’ and 3.6% in ‘‘relieved’’; p = 1.000). Those who stated ‘‘relieved’’ was 41.0% in LL, 2.4% in LS, and 0.0% in SS; the percentage for LL was significantly higher than that for LS or SS (p < 0.001 and p < 0.001, respectively). Those who stated ‘‘anxious’’ was 11.5% in LL, 31.0% in LS, and 41.4% in SS; the percentage for LS or SS was significantly higher than that for LL (p = 0.004 and p < 0.001, respectively). There were no claims or consultations on genotype to the health management section, and serious responses of the genotype-notified participants were not observed throughout the study. 4. Discussion
Table 2 Quitting behavior and stage of change at one year after genotype notification. Notified group N = 257 Quit Not quit No concern No intention Wish to quit No answer No response
Control group (%)
15
N = 276
(5.8)
203 26 162 15 0 39
22
(79.0) (10.7) (66.9) (6.2) (0.0) (16.1)
223 30 176 16 1 31
(%) (8.0) (80.8) (10.9) (63.8) (6.0) (0.4) (11.2)
differences in sex and age distributions between those who agreed and those who refused. Table 2 shows the stage of smokers at one year after the enrollment. Those who stated to have quitted smoking were 22 (8.0%) among the 276 controls and 15 (5.8%) among the 257 genotype notified participants. The difference in the cessation rate between the two groups was not significant (p = 0.395). When 29 smokers who refused genotype tests were regarded as non-quitters, the cessation rate of whole intervention group was 5.2% (p = 0.234 in comparison with the rate among the controls). The OR of cessation for the intervention adjusted by age, sex and stage at enrollment was not statistically significant (OR = 0.64, 95% CI 0.32–1.28, p = 0.209). Among non-quitters, the difference in the stage of smokers at one year after enrollment between the two groups was not significant (x2 = 0.961 d.f. = 3, p = 0.811). In both groups, the subjects in the stage of ‘‘wish to quit’’ (11.8% in the intervention group and 11.1% in the controls) tended to have a high cessation rate compared with ‘‘no concern’’ (0.0% and 4.3%, respectively) or ‘‘no intention’’ (6.2% and 8.2%) group, although statistically not significant.
This study based on the questionnaire found that the cessation rate was 5.8% among the genotype notified participants, and 8.0% in the controls. The rate was not significantly different according to the L-myc genotype. There were no such severe substantial psychological/social problems as to require counseling relating with the genotype notification, although the percentage who stated to ‘‘relieved’’ was significantly low among those with LS or SS relative to those with LL, and that of ‘‘anxious’’ was significantly higher among those with LS or SS relative to those with LL. The genotype frequency of L-myc was 23.7% for LL, 49.0% for LS, and 27.2% for SS among the 257 genotyped participants. The distribution was similar to the other studies in Japanese, for example, 24.5%, 55.6%, and 19.9%, respectively, among 241 noncancer controls [18]. Generally, the cessation rate among health checkup examinees is relatively low; a follow-up study conducted in 1997–1998 reported that one-year cessation rate was 6.0% among 2190 health checkup examinees [24]. Cessation rate was reportedly higher in patients than in healthy individuals, which might be attributable to the high consciousness of the harms of smoking among the patients [25]. In the present study, the controls showed a slightly higher cessation rate (8.0%), possibly because situations surrounding the workplaces were changing against smoking. On August 2 in 2002, Health Promotion Act was issued in Japan, which defines the responsibility of owners/managers to prevent passive smoking at their facilities. Accordingly, the company might be influenced by the Act; a part of smokers might realize that smoking was disadvantageous not only for their health but also for his/her promotion or evaluation at workplace. The reasons for no effects of genotype notification were not clear. It was possible that they had no time to understand the implication of genotype testing and to
Table 3 Cessation rate in the percentage according to L-myc genotype and response of the notified group to the question ‘‘How did you feel when your genotypes were notified?’’. Response
L-myc genotype
Total
LL
LS
N
%
Relieved Anxious Neither Forgot Others No answer/No response
25 7 15 5 3 6
4.0 0.0 6.7 20.0 0.0 0.0
Total
61
4.9
N: number of the notified subjects.
N
SS %
N
%
N
%
3 39 39 17 2 26
0.0 7.7 0.0 11.8 0.0 7.7
0 29 15 14 1 11
0.0 6.9 6.7 14.3 0.0 0.0
28 75 69 36 6 43
3.6 6.7 2.9 13.9 0.0 4.7
126
5.6
70
7.1
257
5.8
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consider the messages from the results. Lack of the knowledge concerning genotype tests might have diminished the effects of the intervention on smoking behavior. In addition, the bank was in the midst of restructuring, so that the majority might have been nervous or under stress, which could have additionally diluted the effects of genotype notification. In this study, the difference in the cessation rate was not significant among those with the different stage of smokers at enrollment possibly due to the limited number of subjects, although the smokers who ‘‘wished to quit’’ showed a trend of a higher cessation rate compared with ‘‘no concern’’ or ‘‘no intention’’ group. The tendency in the intervention group was similar to that in the controls. In the previous reports, the stage of change was a good predictor of smoking cessation [26,27]. The cessation rate according to L-myc genotype revealed no statistically significant difference in this study, however, there still seems to be a possibility that genotype notification could be more effective in those with risky genotypes, and further investigation with larger number of study subjects are required to verify this hypothesis. Although those who stated ‘‘relieved’’ after the notification was more in LL genotype, such response was not strongly related to the cessation rate; 3.6% for ‘‘relieved’’ and 6.7% for ‘‘anxious’’. The high uptake rate (89.9%) of genotype testing might be explained by the fact that this study was conducted in one bank and the workers are cooperative to the research, and another plausible reason may be the regional characteristics of Nagoya citizens who tend to unite and be faithful to authorities like Nagoya University Graduate School of Medicine. There could also be potential harm associated with genotype notification. In this study, any serious problems were not observed. To date, several reports about genotype notification to smokers were made, few of which ever documented such severe problems [10–17], although some reports pointed out that receiving information about own disease risk can be potentially anxiety provoking [28–30]. The response to polymorphism genotype tests might differ from genotype notification of hereditary diseases like BRCA1/BRCA2 mutations in breast cancer [31,32] and cystic fibrosis [33]. A study reported that genotype disclosure to hereditary nonpolyposis colorectal cancer carriers did not demonstrate significant adverse psychological outcomes [34]. In this study, there was no request from the participants to provide genetic counseling or other psychological support, suggesting that the anxieties related to genotype notification were not so severe even in those with the high-risk genotypes. Nevertheless, it will be wise to be careful about the response of the participants after genotype notification. There were several limitations in this study. First, the cessation was not confirmed by a biological test, such as carbon mono-oxide in the breath and nicotine/cotinine concentration in urine. Second, the changes in perception of their disease risk after the genotype notification were not precisely measured, but we evaluated only the association with the final outcome, the stage of change. In this study we also used our original criteria for the stage of change to be suitable for practical application, which should have been replaced with more faithful outcome measures to the original definition by Prochaska et al. [22], although it would be even better if replaced with more recent criteria of transtheoretical model consisting of four constructs: stage of change, decisional balance, self-efficacy, and process of change [35,36]. Third, the emotional burden derived from the genotype notification was not measured with an established questionnaire. In addition, indicators of socioeconomic status like income levels, educational levels, or job title/level were not available in this study mainly in consideration of privacy of the participants. In this study, only the association between genotype notification and its effect on smoking cessation is studied, it would have been better if the effects of genotype notification on more
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detailed behavioral changes such as changes in stages of change were evaluated, and some other factors that can influence smoking cessation rate like age or gender should also have been included in the analyses. The sample size in this study is small, and the number of those with an elevated risk for disease is even smaller, making the possibility to analyze the effect of genotype notification to this high-risk group very limited. Based on these limitations, the findings had to be carefully interpreted. There might be some other factors related to smoking cessation. Nicotine dependence and genetic traits of addiction such as genotypes of dopamine reward pathways were also reported to influence smoking behaviors of the individuals [37,38]. Diagnosis and severity of disease was reported to influence the cessation rate [25,39]. To promote smoking cessation more effectively, it would be necessary to take these factors into consideration. In conclusion, the present study based on the self-administered questionnaire did not show positive effects of genotype notification on smoking cessation. To elevate the cessation rate, methods to explain and notify genotypes should be improved. Furthermore, the combinations to other methods including nicotine replacement therapy needed to be explored. Conflict of interests The authors have no conflict of interests to declare. Acknowledgments This study was supported in part by a Grant-in-Aid for Cancer Research from the Japanese Ministry of Health, Labour and Welfare. References [1] Ebbert JO, Sood A, Hays JT, Dale LC, Hurt RD. Treating tobacco dependence: review of the best and latest treatment options. J Thorac Oncol 2007;2:249–56. [2] Nishino Y, Inoue M, Tsuji I, Wakai K, Nagata C, Mizoue T, et al. Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan. Tobacco smoking and gastric cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol 2006;36:800–7. [3] Nagata C, Mizoue T, Tanaka K, Tsuji I, Wakai K, Inoue M, et al. Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan. Tobacco smoking and breast cancer risk: an evaluation based on a systematic review of epidemiological evidence among the Japanese population. Jpn J Clin Oncol 2006;36:387–94. [4] Eguchi H, Nakachi K. Smoking as a risk factor for pancreatic cancer. Nippon Rinsho 2006;64(Suppl 1):10–3 (in Japanese). [5] Mizoue T, Inoue M, Tanaka K, Tsuji I, Wakai K, Nagata C, et al. Research Group for the Development, Evaluation of Cancer Prevention Strategies in Japan. Tobacco smoking and colorectal cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol 2006;36:25–39. [6] Morgan GD, Backinger CL, Leischow SJ. The future of tobacco-control research. Cancer Epidemiol Biomarkers Prev 2007;16:1077–80. [7] Janz NK, Becker MH. The Health Belief Model: a decade later. Health Educ Q 1984;11:1–47. [8] Witte K. Putting the fear back into fear appeals: the extended parallel process model. Comm Mono 1992;59:329–49. [9] Etchegary H, Perrier C. Information processing in the context of genetic risk: implications for genetic-risk communication. J Genet Couns 2007;16:419– 32. [10] Audrain J, Boyd NR, Roth J, Main D, Caporaso NF, Lerman C. Genetic susceptibility testing in smoking-cessation treatment: one-year outcomes of a randomized trial. Addict Behav 1997;22:741–51. [11] Lerman C, Gold K, Audrain J, Lin TH, Boyd NR, Orleans CT, et al. Incorporating biomarkers of exposure and genetic susceptibility into smoking cessation treatment: effects on smoking-related cognitions, emotions, and behavior change. Health Psychol 1997;16:87–99. [12] McBride CM, Bepler G, Lipkus IM, Lyna P, Samsa G, Albright J, et al. Incorporating genetic susceptibility feedback into a smoking cessation program for African-American smokers with low income. Cancer Epidemiol Biomarkers Prev 2002;11:521–8. [13] Sanderson SC, Humphries SE, Hubbart C, Hughes E, Jarvis MJ, Wardle J. Psycological and behavioural impact of genetic testing smokers for lung cancer risk: a phase II exploratory trial. J Health Psychol 2008;13:481–94.
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