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Association between cigarette smoking and Parkinson’s disease: A meta-analysis
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Association between cigarette smoking and Parkinson’s disease: A meta-analysis Xiao Lia,b , Weihua Lia , Guixia Liua , Xu Shenb , Yun Tanga,* a Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 December 2014 Received in revised form 30 July 2015 Accepted 1 August 2015 Available online xxx
Objective: To evaluate the association of Parkinson’s disease (PD) with smoking, and determine whether gender, source of controls, dose of smoking, and year of studies modify the observed effects of smoking on PD. Methods: Available publications between 1959 and 2014 from PubMed, ScienceDirect, Springer Link and Web of Science databases were searched and carefully selected. Relative risks RR of specific study were weighted to obtain a pooled RR estimate and its 95% confidence interval CI. Results: 61 case-control and 8 cohort studies were included. The pooled RR of PD was 0.59 (95% CI, 0.56–0.62) for ever smokers compared with never smokers. The stratified analyses indicated a somewhat greater impact of smoking on PD risk in cohort studies than in case-control studies, the protective effect was relatively significant in men more than in women and the inverse effect was slightly greater in hospital-based studies than in population-based studies. Furthermore, a significant inverse dose– response relationship was observed for the number of pack-years smoked. The summary RR for those smoking more than 30 pack-years was 0.66 (95% CI, 0.49–0.88), and 0.39 (95% CI, 0.29–0.53) for those smoking less than 30 pack-years. Conclusion: The results demonstrated the inverse association between cigarette smoking and the risk of PD. We suggest that effective drugs for PD might be developed using chemical substances derived from tobacco or tobacco smoke. ã 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cigarette smoking Parkinson’s disease Meta-analysis Pack-year
1. Introduction Parkinson’s disease (PD) is a movement-related neurodegenerative disease commonly existing in elder people, just second to Alzheimer’s disease (De Lau & Breteler, 2006; Lees, Hardy, & Revesz, 2009; Schapira, 2009). With the advent of the era of aging, the prevalence of PD is expected to rise steadily in future (Davie, 2008; Shen & Ji, 2013). If current trends continue, the number of PD cases should be doubled by 2050 (Schapira, 2009). The etiology of PD remains unclear, various factors are believed to be associated with the risk of developing PD, but no causal relationships have been proven. Although the disease appears multifactorial in origin, it might possibly be arisen from a complex interaction between genetics and environment (Quik, 2004). Many risk and protective factors have been investigated in past decades. A number of environmental factors have been associated with an
* Corresponding author. E-mail address: [email protected] (Y. Tang).
increased risk of PD, including pesticide exposure, head injuries and living in the countryside or farming (Maele-Fabry, Hoet, Vilain, & Lison, 2012; Noyce, Bestwick, & Silveira-Moriyama, 2012). Meanwhile, several protective factors have also been investigated, such as coffee and tea drinking (Hernán, Takkouche, Caaman~oIsorna, & Gestal-Otero; Li, Ji, & Shen, 2012). The argument that smoking is harmful to health has been generally accepted (WHO, 2008); however, many epidemiological studies over the past several decades have revealed a reduced risk of developing PD among cigarette smokers. In an earlier meta-analysis including 44 case-control and four cohort studies, Hernán et al. (2002) reported a pooled relative risk (RR) of 0.59 (95% confidence interval, i.e., CI, 0.54–0.63) for ever versus never smokers, 0.39 (95% CI, 0.32–0.47) for current versus never smokers, and 0.80 (95% CI, 0.69–0.83) for past versus never smokers. They also noted that the inverse association between smoking and PD was stronger in cohort studies than in case-control studies, especially for the comparison of past versus never smokers. Allam, Campbell, Castillo, and Navajas (2004) and Allam, Campbell, Hofman, Del Castillo, and Navajas (2004) also reported smiliar results in 2004. However, the
http://dx.doi.org/10.1016/j.archger.2015.08.004 0167-4943/ ã 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004
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effects of gender, dose of smoking and time of study/publication were not taken into account. Furthermore, in the past decade, several new epidemiological studies were reported. In present study, we performed a meta-analysis to evaluate the association between cigarette smoking and PD risk based on casecontrol and prospective cohort studies up to date. In addition, subgroup analysis was stratified by study design, source of controls, gender, pack-year and year of studies. This report summarized the findings from epidemiological studies and quantified the magnitude of those associations. 2. Materials and methods 2.1. Search strategy The system was designed with reference to the “Meta-analysis of Observational Studies in Epidemiology (MOOSE)” guidelines (Stroup, Berlin, & Morton, 2000). We identified available publications (including articles and theses) in English between January 1, 1959 and October 1, 2014 from PubMed, ScienceDirect, Springer Link and Web of Science databases. The following combined text and MeSH (Medical Subject Headings) heading search strategy was used to search the above-mentioned databases: (smoking or tobacco or cigarette) AND (parkinson or PD) AND (case-control or case-referent or retrospective or cohort or follow-up or prospective). We also examined conference proceedings, and the references in the articles retrieved were crosschecked to obtain all relevant publications on the association between cigarette smoking and PD. 2.2. Selection criteria We included those studies in the meta-analysis, which met the following criteria: written in English, presentation of original data, a case–control or cohort design, physician-confirmed diagnosis of
PD, an odds ratio (OR) or RR and its corresponding 95% CI (or there were enough data to calculate these numbers) reported to quantify the association between cigarette smoking and risk of PD, and absence of significant cognitive impairment. If the results of a study had been published in more than one publication, only the one with most complete information was included. 2.3. Data extraction and statistical analysis Two investigators independently extracted data from the selected papers including first author, year of publication, study type (cohort, case-control), number of cases/controls or participants, source of controls (hospital or population), adjusted association measures (RRs or ORs, and 95% CI) that compared PD risk among never smokers with that among ever, past, or current smokers, and adjustment factors. The definition of past, current, and never smoking in this study complied with the authors of the original reports. When a risk estimate and its 95% CI were not available from the article, the unadjusted values were calculated from the published data of the study. Several subgroup analyses were also conducted to investigate the effect of gender, study type, source of controls, year of study, and dose on cigarette smoking in patients with PD. Relative risks (cohort studies) or odds ratios (case-control studies) of specific study were weighted to obtain a pooled RR estimate and its 95% CI. The odds ratios were considered as RRs since the incidence of PD were not common in general population (Zhang & Yu, 1998). We examined the heterogeneity with I2 test. The I2 value describes the percentage of total variation across studies due to heterogeneity rather than chance (Higgins, Thompson, Deeks, & Altman, 2003). If the I2 value was less than 50%, the study was considered as not significantly different (Higgins et al., 2003). The fixed effect model was employed to calculate the summary RR and its 95% CI values across homogeneous studies and the random effect model was used to calculate
Fig.1. Selection of studies for inclusion in the present meta-analysis.
Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004
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the summary RR and its 95% CI values across heterogeneous studies. The possibility of publication bias was assessed using funnel plot test. Statistical computation was performed using the Review Manager 5.3 statistical software.
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studies included were carried out between 1968 and 2014, so the years of 1990, 2000 and 2010 were selected as the demarcation time. As a result, 12, 23, 22, and 5 studies were published in 1968– 1990, 1991–2000, 2001–2010, and 2011–2014, respectively (Table S1).
3. Results 3.2. Analysis of summary estimates 3.1. Search results and characteristics of the included studies The whole workflow of this meta-analysis was illustrated in Fig. 1. At first 9499 articles were retrieved, 9376 ones from database search and the others from references. By looking through the titles and abstracts of the articles, most of them were irrelevant, and only 352 papers were retained to have potentially relevant studies. After full-text reviewing, 75 papers were found containing data on association of cigarette smoking with PD. 4 duplicates and 2 small co-twin controlled studies were then excluded. Finally, 69 articles were obtained to meet all the eligibility criteria and included in the meta-analysis, among which 61 case-control studies and 9 cohort studies were included. Table S1 showed the study characteristics and main outcomes of the case-control studies, which were carried out in nearly twenty countries between 1968 and 2014. The 61 case-control studies enrolled 13,504 diagnosed PD patients and 22,968 non-PD controls. The control groups were quite diverse: patients with other diseases from the hospitals, friends or relatives of PD patients, community members or neighbors of PD patients, or a combination of these groups. The selected characteristics and results of the 9 cohort studies from 8 articles were shown in Table S2. Overall, data for 860,845 individuals were available for the primary analysis, in which there were 3189 PD events. In order to explore the effects of gender, source of controls, pack-year of smoking, and publication year of study on the association of cigarette smoking with PD, several subgroup analyses were performed. Among the studies, 12 ones provided information on male smokers, whereas 9 ones related to female smokers (Table S3). Most of the case-control studies gave out the source of control subjects, among which 26 studies selected the control subjects from hospital (four of them were absent of ever smokers information) and 29 ones were population-based (also four of them were absent of ever smokers information) (Table S1). The cohort studies were also categorized into population-based subgroup (five of them presented the information of ever smokers). 13 studies reported dose-response relationships between PD and cigarette smoking. The largest dose reported was 30 pack-years. Three studies presented the risk estimates for smoking less than 30 pack-years, and four studies presented the risk estimates for smoking more than 30 pack-years (Table S4). The
The summary risk estimates (RRs) for the association between smoking status and PD were shown in Table 1. 61 studies (including both case-control and cohort studies) were included in the pooled analysis for PD rates in ever and never smokers. Fig. 2 showed that the summary risk of ever smoker applying the fixed effect model was 0.59 (95% CI, 0.56–0.62), which suggested that the risk of PD was 41% lower in ever smokers compared with never smokers. These studies had no significant heterogeneity (I2 = 21%). The pooled RR of PD was 0.76 (95% CI, 0.71–0.81) for former smokers and 0.42 (95% CI, 0.38–0.47) for current smokers compared with never smokers. Results of the studies with two different methods both showed out the protective effect of cigarette smoking in PD risks. In cohort studies, the summary RRs for ever-smoker versus never smoker was 0.50 (95% CI, 0.42–0.60). It is lower than that in case-control studies (summary RR = 0.60, 95% CI = 0.57–0.63). Similarly, significantly decreased RRs for current and former smokers were also noted in case-control studies and cohort studies. 3.3. Stratified analysis A serious of subgroup analyses were also performed to explore the effects of gender, source of controls, pack-year of smoking, and publication year of study on the association of cigarette smoking with PD. The stratified analyses results are shown in Table 2. In the stratified analysis by gender, 12 and 9 studies provided the information of male and female subgroups, separately. The meta-analysis results (summary RR = 0.59 (95% CI, 0.52–0.68) for men and RR = 0.69 (95% CI, 0.59–0.81) for women) indicated the protective effect of cigarette smoking in PD risks. In addition, according to the present results this association was relatively more significant in men than in women. The summary RRs for eversmokers were 0.61 (95% CI, 0.57–0.66) according to data from population-based studies and 0.56 (95% CI, 0.50–0.62) according to data from hospital-based studies. A significant inverse dose– response relationship was observed for the number of pack-years smoked. The summary RR for smoking for more than 30 pack-years was 0.66 (95% CI, 0.49–0.88), and that was 0.39 (95% CI, 0.29–0.53) for smoking for less than 30 pack-years. There were no significant differences between publication times. The summary RRs for ever-
Table 1 Pooled relative risks and 95% confidence intervals of smoking and Parkinson’s disease according to smoking status. Smoking status
No. of studies
RR
95% CI
I2 (%)
Analysis model
Ever smokers All studies Case-control studies Cohort studies
61 56 5
0.59 0.60 0.50
0.56–0.62 0.57–0.63 0.42–0.60
21 22 0
Fixed effect model Fixed effect model Fixed effect model
Former smokers All studies Case-control studies Cohort studies
31 23 8
0.76 0.77 0.75
0.71–0.81 0.70–0.85 0.69–0.81
37 43 19
Fixed effect model Fixed effect model Fixed effect model
Current smokers All studies Case-control studies Cohort studies
32 24 8
0.42 0.42 0.33
0.38–0.47 0.37–0.48 0.23–0.46
45 42 59
Fixed effect model Fixed effect model Random effect model
Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004
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Fig. 2. Relative risk and 95% CI from studies of cigarette smoking and the risk of PD (ever smoker versus never smoker).
smokers were 0.60 (95% CI, 0.52–0.69), 0.61 (95% CI,0.55–0.69), 0.58 (95% CI,0.54–0.62), 0.55 (95% CI, 0.45–0.67) according to studies published in 1968–1990, 1991–2000, 2001–2010 and 2011– 2014, respectively. 3.4. Publication bias Funnel plot test was employed to assess the possibility of publication bias in present study. Fig. 3 showed the funnel plot of association between cigarette smoking and PD risk, in which, the logRR from each study is plotted on the horizontal axis, and its standard error is plotted on the vertical axis. Visual inspection of the funnel plot revealed a symmetric distribution of the logRRs plotted against their standard errors. This result indicated the presence of publication bias in our study.
4. Discussion 4.1. Association between cigarette smoking and PD risk Though massive researches have been conducted during the past decades, the etiology of Parkinson’s disease remains unclear. Current studies suggest that a number of environmental risk and protective factors might be linked to PD. Results from the present meta-analyses suggested a strong inverse association between active cigarette smoking and PD, which is in accordance with earlier studies (Hernán et al., 2002; Allam, Campbell, Castillo et al., 2004; Allam, Campbell, Hofman et al., 2004). Compared with never smokers, the risk of PD was 58% lower in current smokers and 41% lower in ever smokers. Heterogeneity and publication bias were absent from analyses
Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004
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Table 2 Stratified analyses of smoking and Parkinson’s disease. Subgroup
No. of studies
RR
95% CI
I2 (%)
Analysis model
Source of controls Population-based Hospital-based
30 22
0.61 0.56
0.57–0.66 0.50–0.62
26 0
Fixed effect model Fixed effect model
Gender Male Female
12 9
0.59 0.69
0.52–0.68 0.59–0.81
43 0
Fixed effect model Fixed effect model
3 4
0.66 0.39
0.49–0.88 0.29–0.53
0 0
Fixed effect model Fixed effect model
12 23 22 5
0.60 0.61 0.58 0.55
0.52–0.69 0.55–0.69 0.54–0.62 0.45–0.67
0 28 30 56
Dose–response 30 pack-years >30 pack-years Year of publication Before 1990 1990–2000 2000–2010 2010–now
Fixed effect model Fixed effect model Fixed effect model Random effect model
Fig. 3. Funnel plot of studies of cigarette smoking and the risk of PD (ever smoker versus never smoker). The log RR from each study is plotted on the horizontal axis, and its standard error is plotted on the vertical axis.
of data based on ever smokers. This association can be identified from both case-control and cohort studies and it was somewhat greater in cohort studies than in case-control studies. Smoking information in cohort studies is likely more accurate and not influenced by recall bias, since smoking is assessed repeatedly and prior to disease onset in these studies. Better exposure assessment also reduces misclassification bias. Therefore, smoking might be more negatively related to PD than estimates from case-control studies (Ritz, Ascherio, & Checkoway, 2007). In stratified analyses, the inverse effect of ever-smoking was slightly greater in hospital-based studies than in populationbased studies. Generally, hospital-based controls are more likely to engage in risk behaviors compared with the health population, this might lead to underestimation of true risk. It is well known that smokers are more prevalent among hospital patients than in the general population because many diseases led to hospitalization are associated with smoking. Since smoking may be a protective factor for PD, it is reasonable that the summary RR for ever-smoking was lower in hospital-based studies than in population-based studies. A significant inverse dose-response relationship was also observed for pack-years smoked. It is interesting that the protective effect of smoking against PD was
relatively greater in men than in women, while the biological basis underlying this gender difference is unclear. In Huxley’s study (Huxley & Woodward, 2011), they found women had a significant 25% increased risk for coronary heart disease conferred by cigarette smoking compared with men, similarly, the precise mechanisms for this difference is unclear. It should be a good topic to reveal the biological mechanisms for why cigarette smoking brings more harmful and less protective effect to women than men. In the stratified analysis by publication year, there were no significant differences between the studies published in different decades. It is the most controversial issue whether the inverse association between smoking and PD is a biologically meaningful one or an artifact of study design. People who doubt the apparent protective association posited several alternative hypotheses: the association in PD patients is an artifact of diagnostic displacement as to the causes of death; the association is an artifact of selective mortality of smokers who are predestined to acquire PD and are killed off by smoking; the association is a result of a cause-andeffect bias in which PD diagnosis leads to decreased smoking; and there should be some unidentified genetic or environmental factors. These explanations have been well argued previously
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(Hernán et al., 2002; Wirdefeldt, Adami, Cole, Trichopoulos, & Mandel, 2011). Such information and selection biases mentioned would not have a substantial impact on the findings of properly conducted follow-up studies with prospective assessment of PD diagnoses, and thus these biases could hardly explain the strong inverse association found in all cohort studies. Furthermore, although the case-control design may be more prone to information and selection biases, the pooled RRs for ever smoking and current smoking (versus never smoking) from case-control studies were only slightly weaker than those from cohort studies, which suggests that these biases are also relatively unimportant in former (Hernán et al., 2002). Confounding by genetic factors has been addressed in twin studies, in which co-twins of cases are used as controls. This type of design controls for genetics as well as shared early environmental factors. Two largest such studies confirmed the inverse association and also reported a dose–response relationship, indicating that confounding by genetic or environmental factors is unlikely (Wirdefeldt et al., 2011; Tanner, Goldman, & Aston, 2002). In general, the validity of the inverse association between PD and active cigarette smoking is supported by the consistency of findings between separate studies with different designs conducted over the past 50 years by different investigators in different countries. This correction is further supported by the apparent detection of a dose-response relationship and by the strength of prospective studies. The results in the present study do not mean that smoking is recommended because of its inverse association with the risk of PD. Many epidemiologic studies have revealed that smoking is a significant cause of major diseases. We suggest that effective drugs for PD might be developed using chemical substances derived from tobacco or tobacco smoke. 4.2. Hypotheses of biological mechanisms At present, several mechanisms for the protective effects of smoking on risk of PD have been proposed. Tobacco and tobacco smoke contain more than 9000 chemical components (Rodgman & Perfetti, 2013), among which nicotine has attracted the most interest as it stimulates dopaminergic neurons, relieves PD symptoms and also possesses a neuroprotective effect (Quik, 2004). Nicotine generally exerts its effects in the peripheral and central nervous systems by stimulating nicotinic acetylcholine receptors (nAChRs) (Quik et al., 2009). Such knowledge has been employed for the development of nAChR drugs with optimal benefits and a minimum of adverse effects for Parkinson's disease management (Mudo, Belluardo, & Fuxe, 2007). Hong et al. investigated the effect of nicotine and the other four compounds of cigarette smoke (anabasine, cotinine, hydroquinone, and nomicotine) on the fibrillation of the a-synuclein protein which aggregates in Lewy bodies of PD among other proteins. Nicotine and hydroquinone did inhibit formation of a-synuclein fibrils, with nicotine being more effective, indicating that these compounds stabilize soluble oligomeric forms of a-synuclein (Hong, Fink, & Uversky, 2009). Several studies proposed that the mono amine oxidase B (MAOB) enzyme, which plays a role in the bioactivation of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is inhibited in the brain of smokers (Schapira, 2011). Recent studies have evaluated specific components of tobacco smoke for their MAO inhibiting and neuroprotective properties (Castagnoli & Murugesan, 2004; Berlin et al., 2012; Carradori et al., 2014). A recent study proposed an interesting hypothesis (Derkinderen, Shannon, & Brundin, 2014), in which cigarette smoke
consumption was said to change the composition of the microbiota in the gut in a way that mitigates intestinal inflammation. This, in turn, would lead to less misfolding of the protein a-synuclein in enteric nerves, reducing the risk of PD by minimizing propagation of the protein aggregates to the central nervous system, where they otherwise can induce neurodegeneration. Actually, the exact molecular mechanism for the protective effects of smoking in PD remains to be clarified, and more researches on these biological mechanisms would be quite necessary. 4.3. Strength and limitations The major strength of this meta-analysis is the size and diversity of studied populations. The consistency in study findings, combined with no evidence of important publication bias, supports the robustness of the study findings. Several limitations of this meta-analysis should be mentioned here. Firstly, only the studies in English language were considered. This may cause omission of relevant studies published in other languages. Secondly, the quality of individual studies included in our study was not always optimal. Thirdly, conversion of ORs to RRs could have underestimated the variance of the RRs derived from ORs. Finally, there is heterogeneity and possibility of publication bias across some stratified analyses. 5. Conclusions In summary, results from our meta-analysis indicated that cigarette smoking was a protective factor against PD risk. The protective effect was somewhat greater in cohort studies than in case-control studies and relatively significant in men rather than in women. It was slightly greater in hospital-based studies than in population-based studies. Furthermore, a significant inverse doseresponse relationship was observed with the number of pack-years smoked. Considering the serious health hazard caused by smoking, we do not recommend smoking to people. However, we may suggest that effective drugs for PD could be developed using chemical substances derived from tobacco or tobacco smoke. In addition, exact molecular mechanism for the protective effect of smoking remains to be clarified. Mechanistic studies in the future will be quite important to understand the role of smoking in PD development, and lead to advances in the prevention and treatment of PD. Role of funding source This work was supported by the Fundamental Research Funds for the Central Universities (Grant WY1113007) and the 111 Project (Grant B07023). Conflict of interest The authors have declared that no conflict of interests exist. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. archger.2015.08.004. References Allam, M. F., Campbell, M. J., Castillo, A. S. D., & Navajas, R. F. (2004). Parkinson’s disease protects against smoking? Behavioural Neurology, 15, 65–71.
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Association between cigarette smoking and Parkinson’s disease: A meta-analysis Xiao Lia,b , Weihua Lia , Guixia Liua , Xu Shenb , Yun Tanga,* a Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 December 2014 Received in revised form 30 July 2015 Accepted 1 August 2015 Available online xxx
Objective: To evaluate the association of Parkinson’s disease (PD) with smoking, and determine whether gender, source of controls, dose of smoking, and year of studies modify the observed effects of smoking on PD. Methods: Available publications between 1959 and 2014 from PubMed, ScienceDirect, Springer Link and Web of Science databases were searched and carefully selected. Relative risks RR of specific study were weighted to obtain a pooled RR estimate and its 95% confidence interval CI. Results: 61 case-control and 8 cohort studies were included. The pooled RR of PD was 0.59 (95% CI, 0.56–0.62) for ever smokers compared with never smokers. The stratified analyses indicated a somewhat greater impact of smoking on PD risk in cohort studies than in case-control studies, the protective effect was relatively significant in men more than in women and the inverse effect was slightly greater in hospital-based studies than in population-based studies. Furthermore, a significant inverse dose– response relationship was observed for the number of pack-years smoked. The summary RR for those smoking more than 30 pack-years was 0.66 (95% CI, 0.49–0.88), and 0.39 (95% CI, 0.29–0.53) for those smoking less than 30 pack-years. Conclusion: The results demonstrated the inverse association between cigarette smoking and the risk of PD. We suggest that effective drugs for PD might be developed using chemical substances derived from tobacco or tobacco smoke. ã 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cigarette smoking Parkinson’s disease Meta-analysis Pack-year
1. Introduction Parkinson’s disease (PD) is a movement-related neurodegenerative disease commonly existing in elder people, just second to Alzheimer’s disease (De Lau & Breteler, 2006; Lees, Hardy, & Revesz, 2009; Schapira, 2009). With the advent of the era of aging, the prevalence of PD is expected to rise steadily in future (Davie, 2008; Shen & Ji, 2013). If current trends continue, the number of PD cases should be doubled by 2050 (Schapira, 2009). The etiology of PD remains unclear, various factors are believed to be associated with the risk of developing PD, but no causal relationships have been proven. Although the disease appears multifactorial in origin, it might possibly be arisen from a complex interaction between genetics and environment (Quik, 2004). Many risk and protective factors have been investigated in past decades. A number of environmental factors have been associated with an
* Corresponding author. E-mail address: [email protected] (Y. Tang).
increased risk of PD, including pesticide exposure, head injuries and living in the countryside or farming (Maele-Fabry, Hoet, Vilain, & Lison, 2012; Noyce, Bestwick, & Silveira-Moriyama, 2012). Meanwhile, several protective factors have also been investigated, such as coffee and tea drinking (Hernán, Takkouche, Caaman~oIsorna, & Gestal-Otero; Li, Ji, & Shen, 2012). The argument that smoking is harmful to health has been generally accepted (WHO, 2008); however, many epidemiological studies over the past several decades have revealed a reduced risk of developing PD among cigarette smokers. In an earlier meta-analysis including 44 case-control and four cohort studies, Hernán et al. (2002) reported a pooled relative risk (RR) of 0.59 (95% confidence interval, i.e., CI, 0.54–0.63) for ever versus never smokers, 0.39 (95% CI, 0.32–0.47) for current versus never smokers, and 0.80 (95% CI, 0.69–0.83) for past versus never smokers. They also noted that the inverse association between smoking and PD was stronger in cohort studies than in case-control studies, especially for the comparison of past versus never smokers. Allam, Campbell, Castillo, and Navajas (2004) and Allam, Campbell, Hofman, Del Castillo, and Navajas (2004) also reported smiliar results in 2004. However, the
http://dx.doi.org/10.1016/j.archger.2015.08.004 0167-4943/ ã 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004
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effects of gender, dose of smoking and time of study/publication were not taken into account. Furthermore, in the past decade, several new epidemiological studies were reported. In present study, we performed a meta-analysis to evaluate the association between cigarette smoking and PD risk based on casecontrol and prospective cohort studies up to date. In addition, subgroup analysis was stratified by study design, source of controls, gender, pack-year and year of studies. This report summarized the findings from epidemiological studies and quantified the magnitude of those associations. 2. Materials and methods 2.1. Search strategy The system was designed with reference to the “Meta-analysis of Observational Studies in Epidemiology (MOOSE)” guidelines (Stroup, Berlin, & Morton, 2000). We identified available publications (including articles and theses) in English between January 1, 1959 and October 1, 2014 from PubMed, ScienceDirect, Springer Link and Web of Science databases. The following combined text and MeSH (Medical Subject Headings) heading search strategy was used to search the above-mentioned databases: (smoking or tobacco or cigarette) AND (parkinson or PD) AND (case-control or case-referent or retrospective or cohort or follow-up or prospective). We also examined conference proceedings, and the references in the articles retrieved were crosschecked to obtain all relevant publications on the association between cigarette smoking and PD. 2.2. Selection criteria We included those studies in the meta-analysis, which met the following criteria: written in English, presentation of original data, a case–control or cohort design, physician-confirmed diagnosis of
PD, an odds ratio (OR) or RR and its corresponding 95% CI (or there were enough data to calculate these numbers) reported to quantify the association between cigarette smoking and risk of PD, and absence of significant cognitive impairment. If the results of a study had been published in more than one publication, only the one with most complete information was included. 2.3. Data extraction and statistical analysis Two investigators independently extracted data from the selected papers including first author, year of publication, study type (cohort, case-control), number of cases/controls or participants, source of controls (hospital or population), adjusted association measures (RRs or ORs, and 95% CI) that compared PD risk among never smokers with that among ever, past, or current smokers, and adjustment factors. The definition of past, current, and never smoking in this study complied with the authors of the original reports. When a risk estimate and its 95% CI were not available from the article, the unadjusted values were calculated from the published data of the study. Several subgroup analyses were also conducted to investigate the effect of gender, study type, source of controls, year of study, and dose on cigarette smoking in patients with PD. Relative risks (cohort studies) or odds ratios (case-control studies) of specific study were weighted to obtain a pooled RR estimate and its 95% CI. The odds ratios were considered as RRs since the incidence of PD were not common in general population (Zhang & Yu, 1998). We examined the heterogeneity with I2 test. The I2 value describes the percentage of total variation across studies due to heterogeneity rather than chance (Higgins, Thompson, Deeks, & Altman, 2003). If the I2 value was less than 50%, the study was considered as not significantly different (Higgins et al., 2003). The fixed effect model was employed to calculate the summary RR and its 95% CI values across homogeneous studies and the random effect model was used to calculate
Fig.1. Selection of studies for inclusion in the present meta-analysis.
Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004
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the summary RR and its 95% CI values across heterogeneous studies. The possibility of publication bias was assessed using funnel plot test. Statistical computation was performed using the Review Manager 5.3 statistical software.
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studies included were carried out between 1968 and 2014, so the years of 1990, 2000 and 2010 were selected as the demarcation time. As a result, 12, 23, 22, and 5 studies were published in 1968– 1990, 1991–2000, 2001–2010, and 2011–2014, respectively (Table S1).
3. Results 3.2. Analysis of summary estimates 3.1. Search results and characteristics of the included studies The whole workflow of this meta-analysis was illustrated in Fig. 1. At first 9499 articles were retrieved, 9376 ones from database search and the others from references. By looking through the titles and abstracts of the articles, most of them were irrelevant, and only 352 papers were retained to have potentially relevant studies. After full-text reviewing, 75 papers were found containing data on association of cigarette smoking with PD. 4 duplicates and 2 small co-twin controlled studies were then excluded. Finally, 69 articles were obtained to meet all the eligibility criteria and included in the meta-analysis, among which 61 case-control studies and 9 cohort studies were included. Table S1 showed the study characteristics and main outcomes of the case-control studies, which were carried out in nearly twenty countries between 1968 and 2014. The 61 case-control studies enrolled 13,504 diagnosed PD patients and 22,968 non-PD controls. The control groups were quite diverse: patients with other diseases from the hospitals, friends or relatives of PD patients, community members or neighbors of PD patients, or a combination of these groups. The selected characteristics and results of the 9 cohort studies from 8 articles were shown in Table S2. Overall, data for 860,845 individuals were available for the primary analysis, in which there were 3189 PD events. In order to explore the effects of gender, source of controls, pack-year of smoking, and publication year of study on the association of cigarette smoking with PD, several subgroup analyses were performed. Among the studies, 12 ones provided information on male smokers, whereas 9 ones related to female smokers (Table S3). Most of the case-control studies gave out the source of control subjects, among which 26 studies selected the control subjects from hospital (four of them were absent of ever smokers information) and 29 ones were population-based (also four of them were absent of ever smokers information) (Table S1). The cohort studies were also categorized into population-based subgroup (five of them presented the information of ever smokers). 13 studies reported dose-response relationships between PD and cigarette smoking. The largest dose reported was 30 pack-years. Three studies presented the risk estimates for smoking less than 30 pack-years, and four studies presented the risk estimates for smoking more than 30 pack-years (Table S4). The
The summary risk estimates (RRs) for the association between smoking status and PD were shown in Table 1. 61 studies (including both case-control and cohort studies) were included in the pooled analysis for PD rates in ever and never smokers. Fig. 2 showed that the summary risk of ever smoker applying the fixed effect model was 0.59 (95% CI, 0.56–0.62), which suggested that the risk of PD was 41% lower in ever smokers compared with never smokers. These studies had no significant heterogeneity (I2 = 21%). The pooled RR of PD was 0.76 (95% CI, 0.71–0.81) for former smokers and 0.42 (95% CI, 0.38–0.47) for current smokers compared with never smokers. Results of the studies with two different methods both showed out the protective effect of cigarette smoking in PD risks. In cohort studies, the summary RRs for ever-smoker versus never smoker was 0.50 (95% CI, 0.42–0.60). It is lower than that in case-control studies (summary RR = 0.60, 95% CI = 0.57–0.63). Similarly, significantly decreased RRs for current and former smokers were also noted in case-control studies and cohort studies. 3.3. Stratified analysis A serious of subgroup analyses were also performed to explore the effects of gender, source of controls, pack-year of smoking, and publication year of study on the association of cigarette smoking with PD. The stratified analyses results are shown in Table 2. In the stratified analysis by gender, 12 and 9 studies provided the information of male and female subgroups, separately. The meta-analysis results (summary RR = 0.59 (95% CI, 0.52–0.68) for men and RR = 0.69 (95% CI, 0.59–0.81) for women) indicated the protective effect of cigarette smoking in PD risks. In addition, according to the present results this association was relatively more significant in men than in women. The summary RRs for eversmokers were 0.61 (95% CI, 0.57–0.66) according to data from population-based studies and 0.56 (95% CI, 0.50–0.62) according to data from hospital-based studies. A significant inverse dose– response relationship was observed for the number of pack-years smoked. The summary RR for smoking for more than 30 pack-years was 0.66 (95% CI, 0.49–0.88), and that was 0.39 (95% CI, 0.29–0.53) for smoking for less than 30 pack-years. There were no significant differences between publication times. The summary RRs for ever-
Table 1 Pooled relative risks and 95% confidence intervals of smoking and Parkinson’s disease according to smoking status. Smoking status
No. of studies
RR
95% CI
I2 (%)
Analysis model
Ever smokers All studies Case-control studies Cohort studies
61 56 5
0.59 0.60 0.50
0.56–0.62 0.57–0.63 0.42–0.60
21 22 0
Fixed effect model Fixed effect model Fixed effect model
Former smokers All studies Case-control studies Cohort studies
31 23 8
0.76 0.77 0.75
0.71–0.81 0.70–0.85 0.69–0.81
37 43 19
Fixed effect model Fixed effect model Fixed effect model
Current smokers All studies Case-control studies Cohort studies
32 24 8
0.42 0.42 0.33
0.38–0.47 0.37–0.48 0.23–0.46
45 42 59
Fixed effect model Fixed effect model Random effect model
Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004
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Fig. 2. Relative risk and 95% CI from studies of cigarette smoking and the risk of PD (ever smoker versus never smoker).
smokers were 0.60 (95% CI, 0.52–0.69), 0.61 (95% CI,0.55–0.69), 0.58 (95% CI,0.54–0.62), 0.55 (95% CI, 0.45–0.67) according to studies published in 1968–1990, 1991–2000, 2001–2010 and 2011– 2014, respectively. 3.4. Publication bias Funnel plot test was employed to assess the possibility of publication bias in present study. Fig. 3 showed the funnel plot of association between cigarette smoking and PD risk, in which, the logRR from each study is plotted on the horizontal axis, and its standard error is plotted on the vertical axis. Visual inspection of the funnel plot revealed a symmetric distribution of the logRRs plotted against their standard errors. This result indicated the presence of publication bias in our study.
4. Discussion 4.1. Association between cigarette smoking and PD risk Though massive researches have been conducted during the past decades, the etiology of Parkinson’s disease remains unclear. Current studies suggest that a number of environmental risk and protective factors might be linked to PD. Results from the present meta-analyses suggested a strong inverse association between active cigarette smoking and PD, which is in accordance with earlier studies (Hernán et al., 2002; Allam, Campbell, Castillo et al., 2004; Allam, Campbell, Hofman et al., 2004). Compared with never smokers, the risk of PD was 58% lower in current smokers and 41% lower in ever smokers. Heterogeneity and publication bias were absent from analyses
Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004
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Table 2 Stratified analyses of smoking and Parkinson’s disease. Subgroup
No. of studies
RR
95% CI
I2 (%)
Analysis model
Source of controls Population-based Hospital-based
30 22
0.61 0.56
0.57–0.66 0.50–0.62
26 0
Fixed effect model Fixed effect model
Gender Male Female
12 9
0.59 0.69
0.52–0.68 0.59–0.81
43 0
Fixed effect model Fixed effect model
3 4
0.66 0.39
0.49–0.88 0.29–0.53
0 0
Fixed effect model Fixed effect model
12 23 22 5
0.60 0.61 0.58 0.55
0.52–0.69 0.55–0.69 0.54–0.62 0.45–0.67
0 28 30 56
Dose–response 30 pack-years >30 pack-years Year of publication Before 1990 1990–2000 2000–2010 2010–now
Fixed effect model Fixed effect model Fixed effect model Random effect model
Fig. 3. Funnel plot of studies of cigarette smoking and the risk of PD (ever smoker versus never smoker). The log RR from each study is plotted on the horizontal axis, and its standard error is plotted on the vertical axis.
of data based on ever smokers. This association can be identified from both case-control and cohort studies and it was somewhat greater in cohort studies than in case-control studies. Smoking information in cohort studies is likely more accurate and not influenced by recall bias, since smoking is assessed repeatedly and prior to disease onset in these studies. Better exposure assessment also reduces misclassification bias. Therefore, smoking might be more negatively related to PD than estimates from case-control studies (Ritz, Ascherio, & Checkoway, 2007). In stratified analyses, the inverse effect of ever-smoking was slightly greater in hospital-based studies than in populationbased studies. Generally, hospital-based controls are more likely to engage in risk behaviors compared with the health population, this might lead to underestimation of true risk. It is well known that smokers are more prevalent among hospital patients than in the general population because many diseases led to hospitalization are associated with smoking. Since smoking may be a protective factor for PD, it is reasonable that the summary RR for ever-smoking was lower in hospital-based studies than in population-based studies. A significant inverse dose-response relationship was also observed for pack-years smoked. It is interesting that the protective effect of smoking against PD was
relatively greater in men than in women, while the biological basis underlying this gender difference is unclear. In Huxley’s study (Huxley & Woodward, 2011), they found women had a significant 25% increased risk for coronary heart disease conferred by cigarette smoking compared with men, similarly, the precise mechanisms for this difference is unclear. It should be a good topic to reveal the biological mechanisms for why cigarette smoking brings more harmful and less protective effect to women than men. In the stratified analysis by publication year, there were no significant differences between the studies published in different decades. It is the most controversial issue whether the inverse association between smoking and PD is a biologically meaningful one or an artifact of study design. People who doubt the apparent protective association posited several alternative hypotheses: the association in PD patients is an artifact of diagnostic displacement as to the causes of death; the association is an artifact of selective mortality of smokers who are predestined to acquire PD and are killed off by smoking; the association is a result of a cause-andeffect bias in which PD diagnosis leads to decreased smoking; and there should be some unidentified genetic or environmental factors. These explanations have been well argued previously
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(Hernán et al., 2002; Wirdefeldt, Adami, Cole, Trichopoulos, & Mandel, 2011). Such information and selection biases mentioned would not have a substantial impact on the findings of properly conducted follow-up studies with prospective assessment of PD diagnoses, and thus these biases could hardly explain the strong inverse association found in all cohort studies. Furthermore, although the case-control design may be more prone to information and selection biases, the pooled RRs for ever smoking and current smoking (versus never smoking) from case-control studies were only slightly weaker than those from cohort studies, which suggests that these biases are also relatively unimportant in former (Hernán et al., 2002). Confounding by genetic factors has been addressed in twin studies, in which co-twins of cases are used as controls. This type of design controls for genetics as well as shared early environmental factors. Two largest such studies confirmed the inverse association and also reported a dose–response relationship, indicating that confounding by genetic or environmental factors is unlikely (Wirdefeldt et al., 2011; Tanner, Goldman, & Aston, 2002). In general, the validity of the inverse association between PD and active cigarette smoking is supported by the consistency of findings between separate studies with different designs conducted over the past 50 years by different investigators in different countries. This correction is further supported by the apparent detection of a dose-response relationship and by the strength of prospective studies. The results in the present study do not mean that smoking is recommended because of its inverse association with the risk of PD. Many epidemiologic studies have revealed that smoking is a significant cause of major diseases. We suggest that effective drugs for PD might be developed using chemical substances derived from tobacco or tobacco smoke. 4.2. Hypotheses of biological mechanisms At present, several mechanisms for the protective effects of smoking on risk of PD have been proposed. Tobacco and tobacco smoke contain more than 9000 chemical components (Rodgman & Perfetti, 2013), among which nicotine has attracted the most interest as it stimulates dopaminergic neurons, relieves PD symptoms and also possesses a neuroprotective effect (Quik, 2004). Nicotine generally exerts its effects in the peripheral and central nervous systems by stimulating nicotinic acetylcholine receptors (nAChRs) (Quik et al., 2009). Such knowledge has been employed for the development of nAChR drugs with optimal benefits and a minimum of adverse effects for Parkinson's disease management (Mudo, Belluardo, & Fuxe, 2007). Hong et al. investigated the effect of nicotine and the other four compounds of cigarette smoke (anabasine, cotinine, hydroquinone, and nomicotine) on the fibrillation of the a-synuclein protein which aggregates in Lewy bodies of PD among other proteins. Nicotine and hydroquinone did inhibit formation of a-synuclein fibrils, with nicotine being more effective, indicating that these compounds stabilize soluble oligomeric forms of a-synuclein (Hong, Fink, & Uversky, 2009). Several studies proposed that the mono amine oxidase B (MAOB) enzyme, which plays a role in the bioactivation of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is inhibited in the brain of smokers (Schapira, 2011). Recent studies have evaluated specific components of tobacco smoke for their MAO inhibiting and neuroprotective properties (Castagnoli & Murugesan, 2004; Berlin et al., 2012; Carradori et al., 2014). A recent study proposed an interesting hypothesis (Derkinderen, Shannon, & Brundin, 2014), in which cigarette smoke
consumption was said to change the composition of the microbiota in the gut in a way that mitigates intestinal inflammation. This, in turn, would lead to less misfolding of the protein a-synuclein in enteric nerves, reducing the risk of PD by minimizing propagation of the protein aggregates to the central nervous system, where they otherwise can induce neurodegeneration. Actually, the exact molecular mechanism for the protective effects of smoking in PD remains to be clarified, and more researches on these biological mechanisms would be quite necessary. 4.3. Strength and limitations The major strength of this meta-analysis is the size and diversity of studied populations. The consistency in study findings, combined with no evidence of important publication bias, supports the robustness of the study findings. Several limitations of this meta-analysis should be mentioned here. Firstly, only the studies in English language were considered. This may cause omission of relevant studies published in other languages. Secondly, the quality of individual studies included in our study was not always optimal. Thirdly, conversion of ORs to RRs could have underestimated the variance of the RRs derived from ORs. Finally, there is heterogeneity and possibility of publication bias across some stratified analyses. 5. Conclusions In summary, results from our meta-analysis indicated that cigarette smoking was a protective factor against PD risk. The protective effect was somewhat greater in cohort studies than in case-control studies and relatively significant in men rather than in women. It was slightly greater in hospital-based studies than in population-based studies. Furthermore, a significant inverse doseresponse relationship was observed with the number of pack-years smoked. Considering the serious health hazard caused by smoking, we do not recommend smoking to people. However, we may suggest that effective drugs for PD could be developed using chemical substances derived from tobacco or tobacco smoke. In addition, exact molecular mechanism for the protective effect of smoking remains to be clarified. Mechanistic studies in the future will be quite important to understand the role of smoking in PD development, and lead to advances in the prevention and treatment of PD. Role of funding source This work was supported by the Fundamental Research Funds for the Central Universities (Grant WY1113007) and the 111 Project (Grant B07023). Conflict of interest The authors have declared that no conflict of interests exist. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. archger.2015.08.004. References Allam, M. F., Campbell, M. J., Castillo, A. S. D., & Navajas, R. F. (2004). Parkinson’s disease protects against smoking? Behavioural Neurology, 15, 65–71.
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Please cite this article in press as: X. Li, et al., Association between cigarette smoking and Parkinson’s disease: A meta-analysis, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.08.004