The relationship of cigarette smoking in Japan to lung cancer, COPD, ischemic heart disease and stroke: A systematic review

Background: To present up-to-date meta-analyses of evidence from Japan relating smoking to major smoking-related diseases. Methods: We restricted attention to lung cancer, chronic obstructive pulmonary disease (COPD), ischemic heart disease (IHD) and stroke, considering relative risks (RRs) for current and ex-smokers relative to never smokers. Evidence by amount smoked and time quit was also considered. For IHD and stroke only, studies had to provide age-adjusted RRs, with age-specific results considered. For each disease we extended earlier published databases to include more recent studies. Meta-analyses were conducted, with random-effects RRs and tests of heterogeneity presented. Results: Of 40 studies, 26 reported results for lung cancer and 7 to 9 for each other disease. For current smoking, RRs (95%CIs) were lung cancer 3.59 (3.25-3.96), COPD 3.57 (2.72-4.70), IHD 2.21 (1.96-2.50) and stroke 1.40 (1.25-1.57). Ex-smoking RRs were lower. Data for lung cancer and IHD showed a clear tendency for RRs to rise with increasing amount smoked and decrease with increasing time quit. Dose-response data were unavailable for COPD and unclear for stroke, where the association was weaker. Conclusions: Compared to studies in other Asian and Western countries, current smoking RRs were quite similar for IHD and stroke. The comparison is not clear for COPD, where the Japanese data, mainly from cross-sectional studies, is limited. For lung cancer, the RRs are similar to those in other Asian countries, but substantially lower than in Western countries. Explanations for this are unclear, but less accurate reporting of smoking by Japanese may contribute to the difference.


Introduction
It is well established that the relative risk (RR) of lung cancer from smoking is lower in Japan than in Western populations [1][2][3][4][5] . However, studies of smoking and lung cancer in Japan have proliferated in recent years, and there have been no metaanalyses in the last 10 years, except for a review of prospective studies reported up to 2008 6 . While that review also considered other smoking-related diseases, there have been no other recent comprehensive meta-analyses of the relationship of smoking to chronic obstructive lung disease (COPD) or cardiovascular disease (CVD), based on studies in Japan.
Here we summarize results of Japanese studies relating smoking to lung cancer, COPD, ischaemic (or coronary) heart disease (IHD) and stroke, limiting attention to comparison with never smokers, and considering estimates for current smokers, overall and by amount smoked, and for ex-smokers, overall and by time quit. As we earlier published comprehensive reviews of the evidence for lung cancer 4 and COPD 7 we extend our metaanalyses to include later papers. For IHD and stroke we extend meta-analyses based on studies published from 1990 8 , not attempting to include earlier publications.
Apart from presenting the meta-analysis results, we also briefly compare and contrast the results for Japan with those for other regions, commenting on possible reasons for differences seen.

Methods
This systematic review was conducted according to PRISMA guidelines 9 . A completed PRISMA checklist can be found in Supplementary File 1. Throughout this paper we use the RR to include its various estimates, including the odds ratio and the hazard ratio. Where results are referred to as "significant" without further detail, this implies p<0.05.

Study inclusion and exclusion criteria
We sought studies providing data on RRs for current smokers and/or ex-smokers compared to never smokers for one or more of the diseases lung cancer, COPD, IHD and stroke. Studies providing data from which RRs could be calculated were accepted, as well as those giving the estimates directly.
For lung cancer, attention was restricted to epidemiological prospective or case-control studies involving 100 lung cancers or more, extending our earlier review 4 of studies published in the 1900s. That review considered specific histological types of lung cancer, but here we restrict attention to overall lung cancer. For COPD, cross-sectional studies were also considered, and there was no restriction on number of cases, thus extending an earlier review 7 of studies published before 2007. That review also considered chronic bronchitis and emphysema, but we limit attention to studies using the definitions of COPD described there. We also follow the exclusion criteria given in that review.
For IHD and stroke, we extend an earlier review, described in a supplementary file to a recent publication 8 , which considered studies of prospective or case-control design which involved at least 100 CVD cases and were published between 1990 and 2010. We restricted attention to studies providing data for IHD, acceptable disease definitions including coronary heart disease and acute myocardial infarction, and/or for stroke. Studies providing results only for specific disease subtypes, or only for combined CVD were not included.
While for lung cancer and COPD we accepted studies only providing RRs for the sexes combined, for IHD and stroke the studies had to provide sex-specific RRs. Also for IHD and stroke, studies had to provide RRs adjusted at least for age.

Literature searches
Studies satisfying the specific criteria were first sought from the three earlier reviews 4,7,8 . Additional papers were also sought from recent reviews of the evidence relating quitting smoking to these diseases 10-13 . Finally Medline searches were conducted to update the evidence considered. The searches were conducted along the lines considered in the three earlier reviews 4,7,8 but restricted to Japan and to a later publication date range -from 2000 for lung cancer, from 2007 for COPD, and from 2010 for IHD and stroke, all searches being conducted in early 2017. No attempt was made to consider studies on IHD and stroke published before 1990. In all the searches, abstracts were first examined, with potentially relevant papers then being obtained and examined in detail.

Identification of studies
The earlier reviews 4,7,8,10-13 had already allocated relevant papers to studies, noting multiple papers on the same study, and papers reporting on multiple studies. Similar procedures were carried out to continue this process, with some new publications providing updated information on existing studies. As previously, potential overlaps between studies were noted.

Data recorded
We extended existing databases to include the additional RRs for current or ex-smoking. All estimates considered were for smoking cigarettes only, cigarettes undefined, or any product. The never smoking denominator could include those who never smoked anything, or never smoked cigarettes. RRs were included, where available, for current smoking overall and for sets of RRs grouped by amount smoked, and for ex-smoking overall and for sets of RRs grouped by time quit. As previously, nearequivalent definitions were accepted when exact definitions were not available (e.g. never smokers could include long-term ex-smokers and recent quitters could be treated as current rather than ex-smokers). Given a choice, the RR adjusted for the most potential confounding variables was selected. Sexes-combined RRs were entered only if sex-specific estimates were unavailable. Age-specific RRs were entered, where available, for IHD and stroke, but not for lung cancer or COPD.

Derivation of RRs
Where necessary RRs were derived from data provided using standard methods, as described elsewhere 4 .

Meta-analyses
Fixed-effect and random-effects meta-analyses were calculated using standard methods 14 with between estimated heterogeneity quantified by H, the ratio of the heterogeneity chisquared to its degrees of freedom. This is directly related to the I-squared statistic 15 by the formula I 2 = 100 (H -1)/H. For all meta-analyses, Egger's test of publication bias 16 was also included. Analyses were conducted for current smoking overall and for ex-smoking overall, preferring cigarette only smoking versus never smoking of anything where there was a choice of definition, and also for about 5, 20 and 45 cigarettes currently smoked and about 12, 7 and 3 years quit for ex-smokers. For an RR to be included in these two dose-response analyses, the grouped level had to include the stated value, but not either of the other two. For IHD and stroke, 20 was replaced by 19 in the above scheme for amount smoked so as to maximise usage of the available data.
For current smoking overall and for ex-smoking overall, metaanalyses were conducted separately by sex with the significance of the between sex difference also estimated. Where sufficient data were available, we also conducted tests of variation by levels of other factors, which varied by disease.

Study quality and risk of bias
We did not attempt to derive study-specific scores based on study quality and risk of bias, as the relative importance of different sources of bias or poor quality cannot be reliably assessed. Instead we carried out some meta-analyses showing how estimates varied by aspects of study quality and bias, including study size, number of adjustment variables, and study type. We also considered factors affecting quality and bias in the discussion section.

Searches
For lung cancer, the earlier review 4 included 19 studies conducted in Japan, of which 11 provided relevant data. Three additional relevant studies were reported in the quitting review 11 with a further 12 found from the updated Medline search.
For COPD, the earlier review 7 included four studies in Japan, one rejected as having no relevant data and the results from another later being found to be superseded by a more recent publication. No additional studies were identified in the quitting review 13 but the updated Medline search found four further relevant studies.
For IHD and stroke, the earlier review 8 included four relevant publications, three describing individual studies and one a pooled analysis of three studies. One additional study was identified in the quitting reviews 10,12 , and four additional relevant publications were identified from the Medline search, three describing individual studies and one a pooled analysis of ten studies.
Supplementary File 2 provides fuller details of the literature searches. Table 1 gives details of the 40 studies included in the analyses, presented in order of the date of the publication reporting the relevant results. Of these, the numbers giving results for lung cancer, COPD, IHD and stroke are, respectively, 26, seven, nine and seven, some studies reporting on more than one of these diseases. The table provides information for each study on the study type, the location, the years in which it was conducted, the f Combined results from ten prospective studies, each with at least 10 years follow-up. These included the JACC study. Of the 40 studies, 18 are case-control and 6 of cross-sectional design (all of COPD), with the rest prospective. Ten of the studies were published before 2000, although 20 had been completed by then. The largest study was HIRAYA, which involved 1917 lung cancer cases, 3,548 cases of IHD and 12,732 of stroke, though the SOBUE2 study involved somewhat more lung cancer cases, 2,083. Table 2 gives the RRs for current and ex-smoking while Supplementary File 3 gives them by amount smoked and time quit. As seen in Table 2, most lung cancer estimates are adjusted for age plus at most one other potential confounding variable, while nearly all COPD estimates are unadjusted, even for age. All the IHD and stroke estimates are (as required) adjusted for age, and most of these also for a number of additional variables.

Meta-analyses
Meta-analysis results (random effects estimates) are shown for current smoking in Table 3, for amount smoked by current smokers in Table 4, for ex-smoking in Table 5 and for time quit by ex-smokers in     d Base for comparison is never smoked. The first category for which results are provided includes quit 12 years ago but does not include quit 7 years ago; the second includes quit 7 years ago but does not include quit 3 or 12 years ago; and the third includes quit 3 years ago but does not include quit 7 years ago.

Lung cancer
For current smoking, the overall RR shown in Table 3 is 3.59 (95%CI 3.25-3.96), based on 39 estimates. As shown in Table 2, the RRs range from 1.22 to 6.76, with all but two statistically significant. While the estimates are heterogeneous, no single factor is responsible for this, though (see also Supplementary File 4) there is evidence that RRs are higher in males and where adjusted for more variables. Table 4 shows that the RRs increase steadily with amount smoked, rising from 2.89 (2.44-3.43) for "about 5 cigs/day" to 6.42 (5.14-8.02) for "about 45 cigs/day".
Compared to current smoking the RR for ex-smoking (Table 5) of 2.26 (2.03-2.52) is lower and shows less heterogeneity, with the only factor showing significant variation being publication year, with RRs higher in older (pre-1980) studies. RRs clearly reduced with increasing time of quit, evident both in the individual data sets for each study and the summary analysis in Table 6.

COPD
For current smoking, the overall RR shown in Table 3 is 3.57 (95%CI 2.72-4.70), based on 10 estimates. However, as Table 2 shows, the two RRs from HIRAY2 are atypically high, and excluding these results substantially reduced the heterogeneity and reduced the RR to 3.10 (2.57-3.75). There is no significant variation by sex. Analyses by further subgroups were not attempted, due to the limited number of estimates for which results are available. There are no available results by amount smoked.
For ex-smoking (see Table 5) the overall RR was 3.03 (2.00-4.57). This reduced to 2.16 (1.68-2.77) after excluding the high results from HIRAY2 (Table 2). A single study reported similar RRs for late quitters and early quitters, as shown in the footnote to Table 6.

IHD
For current smoking, the overall RR ( For ex-smoking, the overall RR (Table 5) of 1.46 (1.24-1.71) is clearly lower than that for current smoking. RRs tended to be higher in females, and in less adjusted estimates. In those who had quit for "about 12 years" the RR at 1.22 (0.81-1.84) is not significantly increased, but those for shorter quit times are both elevated to a similar extent (Table 6).

Stroke
For current smoking, the overall RR (Table 3)  There is no clear relationship of risk of stroke to amount smoked (Table 4) though the largest estimate is for the highest dose.
Overall, risk is not significantly elevated in former smokers (Table 5) with the RR estimated as 1.05 (0.96-1.15). However, the analyses show some increase in females, and in short-term quitters (Table 6).

Publication bias
Each meta-analysis included a test of publication bias (detailed results not shown).
For lung cancer, there is no evidence of publication bias for current smoking and only marginal evidence (p<0.05) for ex-smoking, where RRs were somewhat greater in smaller studies. For CVD, the strongest evidence of publication bias (p = 0.003) is for the analysis of current smoking RRs for stroke. This corresponds with the evidence of higher risks in smaller studies.
No evidence of publication bias is seen for COPD for either current or ex smoking.

Avoiding overlap
The meta-analyses reported include all available data, accepting some overlap of results between studies. Some additional analyses were conducted for current smoking either omitting results from the publications reporting combined analyses (3 STUDIES, 10 STUDIES) or omitting results from studies considered in these analyses (JPHC, JACC, MARUG1 ). For CVD it should be noted that omitting the 10 STUDIES results lost relevant information as many of its individual studies were not included elsewhere.

Discussion
The results presented show some increased risk of all four diseases with current smoking, and a lesser increase with ex-smoking, that with stroke not being clearly significant. The evidence for COPD is clearly the thinnest being based largely on cross-sectional studies and on unadjusted RRs, and providing little or no data for amount smoked or time quit. The other diseases do show a tendency for RRs to increase with amount smoked and to decline with increasing time quit, though again the associations are less clear for stroke, the disease most weakly associated with smoking.
In considering these results, various aspects of the data require comment.

Product used
Smoking of tobacco products other than cigarettes, such as cigars or pipes, is rare in Japan 57 and whether authors related results to unspecified smoking, to cigarette smoking or to cigarette only smoking would be of little practical relevance.
Similarly the precise definition of the comparison group, never smokers, is unlikely to be important.

Study type
For lung cancer, there is no evidence that RRs differ between prospective and case-control studies. Since all the RRs for CVD came from prospective studies, and virtually all those for COPD came from cross-sectional studies, variation by study type could not usefully be examined for these diseases.

Subtypes of disease
It was beyond the scope of the study to investigate variation by disease subtypes, though we note that, for lung cancer, some studies (e.g. AKIBA, ITO, MARUG2, JPHC(SOBUE)) present evidence consistent with there being higher RRs for squamous cell carcinoma than for adenocarcinoma.

Age-specific results
It has previously been established that the variation in RR by age is much greater for cardiovascular disease than for lung cancer or COPD 4,7,8 . For this reason we only considered agespecific data for IHD and stroke. The results generally confirmed the higher RRs in younger individuals.

Adjustment for potential confounding variables
In order to limit the scope of the project, attention was restricted to RRs adjusted for the most potential confounding variables where there was a choice. For lung cancer, there was some evidence that more adjusted RRs were higher, but for cardiovascular disease no such trend was seen. RRs for COPD were generally unadjusted.

Outliers
Formal tests for outliers were not attempted, but it was evident from inspection of Table 2 that the very large RRs for the HIRAY2 study were inconsistent with the rest of the available results, and removal of the results from the meta-analysis materially reduced the RRs for both current and ex-smoking. Otherwise there seemed to be no clear outliers, unusually low or high RRs typically having a very wide 95%CI, being based on limited data.

Other issues
Imprecision of the effect estimates could have resulted from errors in diagnosis of disease or errors in determining smoking habits. It was notable that mortality studies generally did not rely on autopsy-confirmed diagnosis, and that smoking habits recorded were usually based on self-report by the individual with no confirmation of non-smoking status by measurement of biomarkers such as cotinine. Table 7 presents meta-analysis relative risks for current smoking by region from this study, from reviews of ours 4,7,8 and from other selected recent reviews 2,6,58-60 chosen as they provided RR estimates for the sexes combined by region. It was clear for IHD that there is little evidence of a material difference in RR between estimates from Japanese studies and those from studies in other Asian countries or Western countries. In all cases the RR is quite close to 2. The pattern is broadly similar for stroke, with the RR for stroke, typically about 1.4, less than that for IHD, with the minor exception of Scandinavia, where the RR is based on only two estimates. For COPD, the available data are limited, but provide some suggestion that, compared to Japan, RRs are somewhat higher for North America though similar for Europe. An international case-control study involving populations in the USA and Japan 3 found no substantial international differences in average daily consumption or mean duration of smoking, but noted that US cases began smoking 2.5 years earlier than Japanese cases. They suggested that possible explanations for the higher smoking risk in the US study may "include a more toxic cigarette formulation of American manufactured cigarettes as evidenced by higher concentrations of tobacco-specific nitrosamines in both tobacco and mainstream smoke, the much wider use of activated charcoal in the filters of Japanese than in American cigarettes, as well as documented differences in genetic susceptibility and lifestyle factors other than smoking." Other authors 1,2,35 have referred to the severe shortage of cigarettes in Japan during and shortly after World War II, the higher incidence of lung cancer in nonsmokers in Japan due to indoor air pollutants (including environmental tobacco smoke), the low fat intake and high intake of several phytochemicals in the Japanese diet, and the lower indoor radon concentrations in Japan than in the USA.

Comparison with results for Western populations
Whether lung cancer risk in nonsmokers in Japan is higher than in Western countries is in any case open to question. A recent publication 61 that indirectly estimated absolute lung cancer mortality rates by smoking status based on a systematic review, found that they were quite similar in Japan to those in most Western countries. For age 70-74 years, mortality rates (per 100,000 per year) in those who had never smoked were estimated as 42.5 (95% CI 34.5-52.4) in Japan based on n = 14 estimates, as compared, for example, to 37.6 (32. One potential explanation for the difference in the relative risk of lung cancer between Asian and Western populations may lie in differences in the accuracy of reporting smoking habits. We are currently involved in a separate project to review accuracy of reporting smoking habits, using cotinine to validate self-reported smoking habits. We are aware of five studies in Asian populations, three in Japan 62-64 , one in Korea 65 and one of South-East Asians resident in the USA 66 , which report results separately for never, ex and current smokers and by sex. All five give results for women, and four do so for men, and the proportion of true current smokers in self-reported never or ex-smokers (as judged by high cotinine levels) in women (range 12.3% to 61.6%, overall 45.8%) is much higher than it is men (range 0.4% to 6.0%, overall 3.4%). The proportion is also much higher than in 13 data sets (five in males, five in females, three in sexes combined) reported in six publications [67][68][69][70][71][72] describing studies in Western populations (England, Finland, Germany, USA) involving large numbers (>2000) of subjects. Here percentages range from 0.4% to 6.1%, with the overall estimates 1.6% for males, 3.2% for females, and 2.3% for the whole sample.
Although the difference is impressive, the percentage that affects the relative risk for current versus never smokers is the proportion of the current smokers in self-reported never smokers. Here the overall percentages are 7.8% in Asian females, 5.5% in Asian males, 1.4% in Western females and 2.3% in Western males. If one assumes that the true RR for current smoking and lung cancer is X, the observed RR based on self-reported data will be X / (1 + (X − 1) p) where p is the proportion of true current smokers among self-reported never smokers. Thus if X = 10, the observed RRs would be 5.9 in Asian females, 6.7 in Asian males, 8.9 in Western females and 8.3 in Western males, based on the data sets investigated. Although there are difficulties in interpreting these results for various reasons, including between-study variation in the body fluids and cut-offs used to determine true smokers, and the possibility that self-reported never smokers who are considered to be current smokers may smoke less than current smokers who admit smoking, we feel that these results suggest that different levels of misclassification of smoking habits between Asian and Western populations may contribute to the lower observed current smoker RRs in Asian populations.

Passive smoking
This review is concerned with the effects of active smoking in Japan on the four diseases concerned. Recent reviews by ourselves [73][74][75][76] and others 77  For lung cancer, the evidence is much more extensive and two recent reviews 73,77 reported very similar overall relative risks for spousal or at home smoking of 1.26 (1.11-1.45) and 1.28 (1.10-1.48) based on 13 or 12 individual estimates, although our review 73 suggested that most, if not all, of the ETS/lung cancer association might be explained by inadequate adjustment for potential confounding by diet and education and by bias due to misclassification of some true smokers as nonsmokers. Even were this association a causal result of exposure to passive smoking it could not explain the substantial difference in active smoking RRs between Asian and Western populations. Not only do the RRs for passive smoking not vary significantly by location 73 , but even if passive smoking exposure were particularly common in Japanese non-smokers, the relatively weak association of passive smoking with lung cancer risk could not possibly explain why active smoking relative risks are two-fold or more higher in Western than in Asian populations.

Conclusions
In Japanese studies, smoking is related to an increased risk of all four diseases studied, though the increase is relatively weak for stroke, and the evidence is limited for COPD. For IHD, the estimated RR for current smoking, of 2.21 (95%CI 1.96-2.50) is similar to that reported in other Asian and in Western populations and is dose-related, increasing with amount smoked and reducing with years quit. For lung cancer, the estimated RR for current smoking of 3.59 (3.25-3.96), which is also clearly dose-related, is similar to that in other Asian populations but substantially less than in Western populations. The explanation of this difference is unclear but high rates of denial of cigarette smoking may contribute.

Data availability
All data underlying the results are available as part of the article and no additional source data are required.
Author information PNL decided on the methodology, checked the literature searches, studied the derivation of the relative risks, carried out the metaanalyses for IHD and stroke, checked the meta-analyses for lung cancer and COPD, and drafted the manuscript. KJC carried out the literature searches and derived the relative risks and checked the meta-analyses for IHD and stroke. AJT derived the relative risks for lung cancer and COPD. BAF carried out the meta-analyses for lung cancer and COPD, and provided detailed comments on early drafts of the paper. All authors read and approved the final manuscript.
Competing interests P N Lee Statistics and Computing Ltd, for whom PNL and KJC are directors, and BAF and AJT are consultants, have for many years carried out work for many different tobacco companies and organizations, including Philip Morris International, the sponsors of this study. The work described here has been carried out independently of the sponsors.

Grant information
Funding was provided by Philip Morris International. The only role they had in the design of the study and collection, analysis, and interpretation of data was to suggest that the review should be conducted and to provide a brief comment on a near final draft of the paper, suggesting only that we refer to our recent publication on indirectly estimated lung cancer rates by smoking status, reference 61 of the submitted paper.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.