Estimates of alcohol-related oesophageal cancer burden in Japan: systematic review and meta-analyses.

OBJECTIVE: To refine estimates of the burden of alcohol-related oesophageal cancer in Japan.
METHODS: We searched PubMed for published reviews and original studies on alcohol intake, aldehyde dehydrogenase polymorphisms, and risk for oesophageal cancer in Japan, published before 2014. We conducted random-effects meta-analyses, including subgroup analyses by aldehyde dehydrogenase variants. We estimated deaths and loss of disability-adjusted life years (DALYs) from oesophageal cancer using exposure distributions for alcohol based on age, sex and relative risks per unit of exposure.
FINDINGS: We identified 14 relevant studies. Three cohort studies and four case-control studies had dose-response data. Evidence from cohort studies showed that people who consumed the equivalent of 100 g/day of pure alcohol had an 11.71 fold, (95% confidence interval, CI: 2.67-51.32) risk of oesophageal cancer compared to those who never consumed alcohol. Evidence from case-control studies showed that the increase in risk was 33.11 fold (95% CI: 8.15-134.43) in the population at large. The difference by study design is explained by the 159 fold (95% CI: 27.2-938.2) risk among those with an inactive aldehyde dehydrogenase enzyme variant. Applying these dose-response estimates to the national profile of alcohol intake yielded 5279 oesophageal cancer deaths and 102,988 DALYs lost - almost double the estimates produced by the most recent global burden of disease exercise.
CONCLUSION: Use of global dose-response data results in an underestimate of the burden of disease from oesophageal cancer in Japan. Where possible, national burden of disease studies should use results from the population concerned.

Introduction

Alcohol consumption is a major contributor to the global burden of disease, and is a major risk factor for cancer.– Of all alcohol-related cancers, oesophageal has the highest alcohol-attributable fraction – i.e. the highest proportion of these cancers would be prevented if no alcohol were consumed.– The global burden of disease (GBD) study estimates that in 2010 alcohol-attributable oesophageal cancer resulted in 76 700 deaths and 1 825 000 disability adjusted life years (DALYs) lost, globally.

A large portion of oesophageal cancers attributable to alcohol consumption occur in Asian countries – 52.2% (40 000) of all alcohol-attributable oesophageal cancer deaths and 51.8% (945 000) of all alcohol-attributable oesophageal cancer DALYs. The alcohol-attributable portions for countries in this region have been calculated based on global meta-analyses., However, this assumes that the alcohol-attributable risk for oesophageal cancer is the same in all regions. Preliminary evidence, on the other hand, shows that the risk for this cancer is different for people of Asian origin, because of genetic polymorphisms – most importantly the aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) polymorphisms.– Thus, the real risk and burden of alcohol-attributable oesophageal cancer in Asia may have been underestimated.

In Japan in 2010, oesophageal cancer was among the top 20 causes of years of life lost (11 deaths and 181 DALYs per 100 000 people per year). We did a systematic review and meta-analyses of studies conducted in the Japanese population to estimate the alcohol-attributable burden of oesophageal cancer. We then compared these estimates to the GBD 2010 estimates. We also estimated risk functions according to ALDH2 subsets and investigated potential interactions between ALDH2 and ADH1B polymorphisms.

Methods

Data search and selection

We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. We used the latest editions of the International Agency for Research on Cancer (IARC) monographs on alcohol, to identify potentially eligible studies. Additionally, we searched PubMed for publications published before 2014. We did two searches using the following search terms; Search 1: “cancer or neoplasm or carcinom*” and “ALDH2 or ADH1B or ADH2 or ADH3 or ADH1C or dehydrogenase*” and “alcohol or ethanol”; Search 2: “alcohol or ethanol” and “cohort” and “cancer” and “japan” and “review” and “mortality”. Inclusion criteria for analyses investigating the relationship between alcohol consumption, ALDH2, and oesophageal cancer were: (i) prospective or historical cohort or case-control study design; (ii) a measure of risk and its corresponding measure of variability was reported or there were sufficient data for us to calculate these; (iii) oesophageal cancer was reported as a separate outcome; (iv) data on total alcohol intake for at least two exposure categories among current drinkers, or estimates for ALDH2 variants by alcohol intake were reported; (v) risk estimates were at least age-adjusted; and (vi) the study was conducted in Japan after 1980. In addition, we searched reference lists of identified articles for additional articles. No active filters or language restrictions were applied. We excluded measures of pure drinking frequency and qualitative characteristics – such as social or problem drinker. Oesophageal cancer cases (International Classification of Diseases [ICD] version 9: 150, ICD-10: C15) were defined as newly diagnosed at the first visit to a specialized clinic, through cancer registries or cause of death on death certificates.

Most quality scores for primary studies are tailored for meta-analyses of randomized trials of interventions– and many criteria for such scores do not apply to epidemiological studies examined in this study. Additionally, quality score use in meta-analyses remains controversial., As a result, we included quality components in the inclusion and exclusion criteria of the systematic search and separate meta-analyses – such as study design and alcohol measurement – and conducted subgroup analyses based on study design and genetic polymorphisms.

Data extraction

From all relevant articles we extracted: authors’ names, year of publication, country, calendar year(s) of baseline examination, follow-up period, setting, assessment of oesophageal cancer diagnosis, range of age at baseline, sex, number of observed oesophageal cancer cases among participants by alcohol exposure category, number of total participants by alcohol exposure category, adjustment for potential confounders and effect size with its standard error. We used the most fully adjusted effect size reported and selected estimates where lifetime abstainers were used as the risk reference group when those were available. Assessment of full-text articles with uncertain eligibility and data abstraction were conducted independently by two authors who discussed differences until consensus was reached. When there was not enough information presented in the article, we contacted the corresponding author.

We converted alcohol intake into grams of pure alcohol per day (g/day) using the midpoints (mean) of reported categories in the studies. For open-ended categories of alcohol intake, we added three-fourths of the previous category’s range to the lower bound of the open-ended categories. We used reported conversion factors in the studies when standard drinks were the unit of measurement. Hazard ratios and odds ratios were assumed to be equivalent to relative risks (RR). We used fractional polynomials to derive the best fitting function for average alcohol consumption in g/day using the pool-first approach described by Orsini et al. Linear and first-degree models were estimated using the following range of powers: −2, −1, 0, 1, 2, 3. Significant increases in deviance were determined by likelihood ratio tests with one degree of freedom.

Data analyses

We conducted several meta-analyses and used the most comprehensive data available separately for each analysis when multiple reports from the same cohort were published. For studies providing data on two or more alcohol intake categories among current drinkers, we pooled data from (i) cohort studies; (ii) case-control studies; (iii) case-control studies that provided stratified data by ALDH2 variants. We conducted sensitivity analyses on the interaction between variants of ADH1B within the genetic variants of ALDH2. In analyses investigating ALDH2 variants, studies were pooled separately for the active variant (ALDH2*1/*1) and inactive variants (ALDH2*1/*2 and ALDH2*2/*2). No cohort studies provided ALDH2 genotype data. Where possible, we avoided ALDH2*2/*2 variants because of the low number of cases. No systematic information on the distribution of ALDH2 variants by drinking level was available and we therefore used the distribution of drinking by ALDH2 variants among controls in case-control studies to estimate this distribution at the population level. Finally, studies were pooled using DerSimonian-Laird random-effect models to allow for between-study heterogeneity. Variation in the effect size other than chance because of heterogeneity between studies was quantified using the I statistic. We conducted meta-regression analyses to identify study characteristics that influenced the association between alcohol consumption and oesophageal cancer risk. Because of few available studies, we were only able to investigate study design in such meta-regression analyses. Examination of potential publication bias using Egger’s regression-based test was planned, but was not done because of the few studies included. All meta-analyses were conducted on the natural log scale in Stata statistical software, version 12.1 (StataCorp. LP, College Station, United States of America) and P < 0.05 (two-sided) was considered statistically significant.

We estimated deaths and DALYs lost from oesophageal cancer attributable to alcohol consumption in Japan applying a standardized alcohol-attributable fraction method using the statistical software package R, version 3.0.3 (R Foundation for Statistical Computing, Vienna, Austria). These deaths and DALYs were estimated by comparing the risk difference of oesophageal cancer under current conditions compared to the risk of oesophageal cancer under the theoretical-minimum-risk exposure scenario where no one has consumed alcohol., These calculations combine information on the prevalence of alcohol consumption adjusted for per capita consumption and RRs for oesophageal cancer. Lifetime abstainers were used as the reference group and compared to former drinkers and current drinkers – by average daily alcohol consumption. Data on alcohol drinking status were obtained from the 2010 GBD study, where data on drinking status were based on data from large population surveys. Data on per capita consumption were from the Global Information System on Alcohol and Health. Calculations for Japan were based on RRs from this study and RRs for GBD estimates for Japan were based on Corrao et al.

Results

After removal of duplicates, we evaluated 1333 records for inclusion in our study. Based on titles and abstracts, we excluded 1174 articles and screened 159 in full-text articles (Fig. 1). After excluding duplicate reports of the same cohorts, we analysed 11 case-control studies– and 3 cohort studies.– Eight case-control and cohort studies–,– reported estimates for at least two alcohol intake categories in comparison to non-drinkers. These studies were used for a nonlinear dose–response analysis of oesophageal cancer risk, including stratified analyses by ALDH2 variants. Four case-control studies– provided indirect evidence for only one alcohol intake category Table 1 (available from: http://www.who.int/bulletin/volumes/93/5/14-142141). In total five studies had data on ALDH2 and ADH1B variants stratified or adjusted by level of alcohol consumption.,,–

Fig. 1

Flowchart for the selection of studies on alcohol consumption and oesophageal cancer in Japan

Table 1

Summary of studies assessing the relationship between alcohol and oesophageal cancer in Japan

Study and year	Study design (follow-up)	Setting	Study period, age and sex	No. of cases and controls	Case and control identification	Alcohol assessment	Adjustment
Yokoyama et al., 199828	Case-control	National Institute on Alcoholism, Kurihama National Hospital	1987–1997, ≥ 40 years, men	Cases: 87, whereof ALDH2*1/*1: 41, ALDH2*1/*2 and ALDH2*2/*2: 46Controls: 487	Cases: SCC histologically diagnosed at alcohol treatment entry or before onset of alcoholismControls: cancer-free alcoholics	Alcohol dependence (DSM-III), mean alcohol intake 123 g/day	Age at admission to alcohol treatment, daily alcohol consumption, number of cigarettes
Takezaki et al., 200035	Case-control	Aichi Cancer Centre	1988–1997, 40–79 years, men	Cases: 284Controls: 11 384 (former alcohol drinkers were excluded in the analysis)	Cases: first out-visit outpatients diagnosed with primary cancer of the oesophagus (ICD-9: 150, ICD-10: C15)Controls: first-visit outpatients confirmed to be cancer-free (including no history of cancer assessed by questionnaire)	Drinking levels: never or occasionally, former drinkers, current drinkers < 1.5 drinks/day, ≥ 1.5 drinks/day. One drink = 1 go (Japanese sake with 27 mL ethanol)	Age, year and season of visit, smoking (never, former, current, < 30 and ≥ 30 pack-years), consumption of raw vegetables
Yokoyama et al., 200129,a	Case-control	National Institute on Alcoholism, Kurihama National Hospital	1993–2000, ≥ 40 years, men	Cases: 112, whereof ALDH2*1/*1: 50, ALDH2*1/*2 and ALDH2*2/*2: 62Controls: 526	Cases: SCC histologically diagnosed at alcohol treatment entry or before onset of alcoholismControls: cancer-free alcoholics	Alcohol dependence (DSM-III), mean alcohol intake 123 g/day	Age at admission to alcohol treatment, daily alcohol consumption, number of cigarettes
Matsuo et al., 200130	Case-control	Aichi Cancer Centre	1984–2000, 40–76 years, women and men	Cases: 102, whereof ALDH2*1/*1: 35, ALDH2*1/*2: 66, ALDH2*2/*2: 1Controls: 241	Cases: first diagnosis for oesophageal cancerControls: first-visit outpatients confirmed by gastroscopy to have no oesophagus or stomach cancer	Drinking status (2 categories): > 3 go (Japanese sake with 75 mL pure alcohol)/day ≥ 5 times per week, and all others (non-drinkers and drinkers with ≤ 3 go per day and < 5 times per week)	Age, smoking (never, former, current, < 30 and ≥ 30 pack-years), consumption of raw vegetables
Yokoyama et al., 200236,a	Case-control	National Cancer Centre Hospital, National cancer Centre Hospital East, Kawasaki Municipal Hospital, National Osaka Hospital	2000–2001, 40–79 years, men	Cases: 220 SCC, whereof ALDH2*1/*1: 60, ALDH2*1*2: 160Controls: 590	Cases: SCC newly diagnosed by histology within 3 years before registration in studyControls: cancer-free men who visited two Tokyo clinics for annual health check-up	Drinking levels: non- or rare drinkers, former drinkers, current drinkers 1–8.9 U/week, 9–17.9 U/week, ≥ 18 U/week. U = unit of alcohol (1 serving of sake, 22 g pure alcohol/U)	Age, frequency of drinking strong alcoholic beverages, smoking (pack years), intake frequency of green-yellow vegetables, intake frequency of fruits
Yokoyama et al., 200332	Case-control	National Cancer Centre Hospital, National cancer Centre Hospital East, Kawasaki Municipal Hospital, National Osaka Hospital	2000–2001, 40–79 years, men	Cases: 220 SCCControls: 598 (former alcohol drinkers were excluded in the analysis)	Cases: SCC newly diagnosed by histology within 3 years before registration in studyControls: cancer-free men who visited two Tokyo clinics for annual health check-ups	Drinking levels: non- or rare drinkers, former drinkers, current drinkers 1–8.9 U/week, 9–17.9 U/week, ≥ 18 U/week. U = unit of alcohol (1 serving of sake, 22 g pure alcohol/U)	Age, frequency of drinking strong alcoholic beverages, smoking (pack years), intake frequency of green-yellow vegetables, intake frequency of fruits
Nakaya et al., 200540	Cohort (7 years follow-up)	Miyagi II	1990–1997, 40–64 years, men	Cases: 48 among 19 607 participants (former alcohol drinkers were excluded in the analysis)	Cases were identified via record linkage to cancer registry	Drinking levels: five categories based on drinking frequency and amount per occasion: never, former-drinkers, current drinkers < 22.8 g pure alcohol/day, 22.8–45.5 g/day, and ≥ 45.6 g/day	Age, smoking (never, former, current 1–19 cigarettes per day, 20–29 per day, 30 or more per day), education, daily consumption of orange and other fruit juice, spinach, carrot or pumpkin, and tomato
Yokoyama et al., 200633	Case-control	National Cancer Centre Hospital, National cancer centre Hospital East, Kawasaki Municipal Hospital, National Osaka Hospital	2000–2004, 40–79 years, women	Cases: 43 SCC, whereof ALDH2*1/*1: 25, ALDH2*1/*2: 18Controls: 365	Cases: SCC newly diagnosed by histology within 3 years before registration in studyControls: cancer-free women who visited two Tokyo clinics for annual health check-up	Drinking levels: non- or rare drinkers, former drinkers, current drinkers 1–8.9 U/week, 9–17.9 U/week, ≥ 18 U/week. U = unit of alcohol (1 serving of sake, 22 g pure alcohol/U)	Age, smoking (pack years), intake frequency of green-yellow vegetables, intake frequency of fruits, preference for hot food or drinks
Ozasa et al., 200741	Cohort (not reported)	JACC	1988–1990, 40–79 years, men	Cases: 117 among 42 578 participants (former alcohol drinkers were excluded)	Death certificates (ICD-10: C15)	Drinking levels: non- or rare drinkers, former drinkers, current drinkers < 54 mL pure alcohol/day, 54–80 mL/day, ≥ 81 mL/day	Age, study area
Cui et al., 200931,a	Case-control	Biobank Japan	2003–2008, 35–85 years, men and women	Cases: 1 066, whereof ALDH2*1/*2: 735, ALDH2*1/*1 and ALDH2*2/*2: 331Controls: 2 761	Cases: histologically diagnosed SCCControls: volunteers or registered in Biobank for diseases other than cancer	Drinking status: none/rare (0–96.5 g pure alcohol/week), and other drinkers (≥ 96.5 g/week)	Age, gender (analyses among heavy alcohol consumers, > 96.5 g/week)
Ishiguro et al., 200939	Cohort (14 years follow-up)	JPHC I+II	1990 and 1993, 40–59 years, men	Cases: 215 SCC among 60 876 participants	Active patient notification from hospital and linkage to Cancer Registry (ICD-0–3: C15.0–15.9)	Drinking levels: non-drinkers, less than weekly drinking (frequency only), 1–149 g pure alcohol /week, 150–299 g/week, ≥ 300 g/week	Age, study area, body mass index, preference for spicy food and drinks, smoking status (never, past, current), flushing response
Oze et al., 201034	Case-control	Aichi Cancer Centre	2001–2005, ≥ 18 years, men and women	Cases: 260, whereof ALDH2*1/*1: 67, ALDH2*1/*2 and ALDH2*2/*2: 198Controls: 487	Cases: first out-visit outpatients diagnosed with primary cancer of the oesophagus (ICD-10: C15)Controls: First-visit outpatients confirmed to be cancer-free (including no history of cancer assessed by questionnaire)	Drinking levels: never, moderate (≤ 4 days/week), high-moderate (≥ 5 days/week and < 46 g pure alcohol/occasion), heavy (≥ 5 days/week and ≥ 46 g/occasion)	Frequency matched by age group (< 40, 40–49, 50–59, 60–69, ≥ 70 years) and sex. Adjustment for cumulative smoking, facial flushing, fruit and vegetable intake, frequent intake of hot beverages and body mass index
Yang et al., 200537,a	Case-control	Aichi Cancer Centre	2000–2004, 18–79 years, men and women	Cases: 165, whereof ALDH2*1/*1: 38, ALDH2*1/*2 and ALDH2*2/*2: 127Controls: 495	Cases: histologically diagnosed with primary cancer of the oesophagus (159 SCC, 6 adenocarcinomas)Controls: first-visit outpatients confirmed to be cancer-free (including no history of cancer assessed by questionnaire)	Drinking levels: non-drinker, non-heavy drinkers (< 5 drinking days/week and < 50 g pure alcohol/occasion) and heavy drinkers (drinking ≥ 5 days/week and ≥ 50 g pure alcohol/occasion) were adjusted for in regression model as reported	Age, sex, smoking, drinking
Tanaka et al., 201038a	Case-control	Juntendo University Hospital, National Cancer Center Hospital, Kurume University Hospital, Saitama Cancer Center, Kagoshima University Hospital, Kyushu University Hospital	2000–2008, 35–85 years, men and women	Cases: 742, whereof ALDH2*1/*1: 194, ALDH2*1/*2 and ALDH2*2/*2: 548Controls: 820	Cases: pathologically newly diagnosed SCCControls: healthy controls without cancer history recruited from Kyushu University and Hospital and related hospitals	Drinking levels: Non-drinker and ever drinkers	Sex, age, study area

ADH1B: alcohol dehydrogenase 1B; ALDH2: aldehyde dehydrogenase 2; DSM: diagnostic statistical manual; ICD: International Classification of Diseases; JACC: Japan collaborative cohort study; JPHC: Japan public health centre-based prospective study; SCC: squamous cell carcinoma of the oesophagus.

a Included in the sensitivity analysis on interaction between ALDH2 and ADH1B on oesophageal cancer risk in Japan.

Note: ALDH2*2/*2 was excluded in our analyses where possible because of the low number of cases.

ADH1B: alcohol dehydrogenase 1B; ALDH2: aldehyde dehydrogenase 2.

As shown in Fig. 2, the risk for oesophageal cancer identified in cohort studies from Japan– was higher compared with the most recent GBD estimate (RR: 11.71; 95% confidence interval, CI: 2.67–51.32 and RR: 3.59; 95% CI: 3.34–3.87, respectively at 100 g/day of pure alcohol intake). The risk identified in case-control studies– (RR: 11.88; 95% CI: 4.41–31.99 at 50 g/day of pure alcohol intake; RR: 33.11; 95% CI: 8.15–134.43 at 100 g/day of pure alcohol intake) was much higher than the Japanese cohort studies or GBD estimates. In a meta-regression, the difference between case-control studies and cohort studies was significant (P = 0.014). We observed moderate heterogeneity among cohort studies (I = 60%, P = 0.082), and high heterogeneity among case-control studies (I = 89%, P < 0.001).

Fig. 2

Risk curves for alcohol consumption and oesophageal cancer risk based on Japanese studies or the Global Burden of Disease 2010 study

GBD: Global Burden of Disease; RR: relative risk.

The risk curves by ALDH2 variants in Japan are displayed in Fig. 3. Three case-control studies,, provided dose–response data for an investigation of ALDH2 polymorphisms in reference to non-drinkers: ALDH2*1/*2 (372 cases) and ALDH2*1/*1 (151 cases). Inactive variants of ALDH2 enzyme showed markedly higher risks with increasing alcohol consumption. The RR compared to non-drinkers was 36.15 (95% CI: 10.34–126.40) at 50 g/day of pure alcohol and 159 (95% CI: 27.2–938.2) at 100 g/day of pure alcohol intake among people carrying the ALDH2*1/*2 variant. In comparison, the RR among those carrying the ALDH2*1/*1 variant was 2.99 (95% CI: 1.75–5.12) at 50 g/day of pure alcohol intake and 8.94 (95% CI: 3.05–26.23) at 100 g/day of pure alcohol. Based on two studies that included people with alcohol dependence (median 120 g/day of pure alcohol intake), people with the inactive variant of ALDH2 had an RR of 13.00 (95% CI: 8.99–18.80) compared to those with the active variant., We interpolated this difference in risk in the curve for ALDH2*1/*2 in Fig. 3, and held the risk increase among people with this ALDH2 variant constant beyond 100 g/day of pure alcohol intake because there were insufficient data to reliably estimate this risk function. Once case-control studies were stratified by ALDH2 variant, there was little or no heterogeneity (ALDH2*1/*1, I = 0%, P = 0.78; ALDH2*1/*2, I = 44%, P = 0.17). Another two studies,, although they did not provide data in reference to non-drinkers, were in close agreement with our reported risk functions.

Fig. 3

Risk curves for alcohol consumption and oesophageal cancer risk based on aldehyde dehydrogenase 2 polymorphisms, Japan

ALDH2: aldehyde dehydrogenase 2; RR: relative risk.

Note: ALDH2*1/*1 corresponds to an active enzyme and ALDH2*1/*2 corresponds to an inactive enzyme.

With regard to differences in risk curves by study design, Table 2 shows that among case-control studies with multiple alcohol intake categories, 72% (350/483) of oesophageal cancer cases among drinkers occurred in 32% (313/980) of the drinking population, namely individuals with the genetic variant ALDH2*1/*2. When the risk curves from case-control studies (Fig. 3) were combined (weighted by their distribution of alcohol consumption by ALDH2 variants at the population level) the risk functions from case-control and cohort studies almost entirely overlapped (Fig. 4). Combining adjusted case-control and cohort studies, at 100 g/day pure alcohol intake, the risk in Japan was markedly elevated (RR: 11.65, 95% CI: 4.16–32.62) compared to GBD estimates (RR: 3.55, 95% CI: 3.30–3.82) (Fig. 5).

Table 2

Distribution of alcohol consumption and the ALDH2 polymorphism in individuals with oesophageal cancer and study controls, Japan

Polymorphism	Alcohol consumption, No. of individuals (%)
	Non-drinker	0–25 g/day	> 25–75 g/day	> 75 g/day	Total
Controls
ALDH2*1/*2	336 (52)	234 (36)	51 (8)	28 (4)	649 (100)
ALDH2*1/*1	145 (18)	350 (43)	231 (28)	86 (11)	812 (100)
Oesophageal cancer cases
ALDH2*1/*2	22 (6)	94 (25)	180 (48)	76 (20)	372 (100)
ALDH2*1/*1	18 (12)	35 (23)	61 (40)	37 (25)	151 (100)

ALDH2: aldehyde dehydrogenase 2.

Note: The ALDH2*1/*1 corresponds to an active enzyme and ALDH2*1/*2 corresponds to an inactive enzyme.

Data sources: Yokoyama et al. Yokoyama et al. Oze et al.

Fig. 4

Risk curves for alcohol consumption and oesophageal cancer risk adjusted for aldehyde dehydrogenase 2 polymorphisms, Japan

Fig. 5

Risk curves for alcohol consumption and oesophageal cancer risk based on Japanese studies adjusted for aldehyde dehydrogenase 2 polymorphisms and the Global Burden of Disease 2010 study

ALDH2: aldehyde dehydrogenase 2; RR: relative risk.

Notes: ALDH2*1/*1 corresponds to an active enzyme and ALDH2*1/*2 corresponds to an inactive enzyme. The relative risk curves by study design overlap almost completely after adjustment for drinking levels at the population level by ALDH2 variants.

ALDH2: aldehyde dehydrogenase 2; RR: relative risk.

To investigate the interaction between ALDH2 and ADH1B gene variants, we performed a sensitivity analysis using five of the 11 identified case-control studies.,,– Regardless of ALDH2 variant, the pooled RRs were higher for Japanese with the slow-acting ADH1B*1/*1 variant than for Japanese with the fast-acting ADH1B*1/*2 or *2/*2 variants. The RR was 3.99 (95% CI: 2.41–6.61; I2 = 81%, P < 0.001) and 2.40 (95% CI: 1.92–3.16; I2 = 1%, P = 0.40) for individuals with an inactive and active ALDH2, respectively (Fig. 6 and Fig. 7).

Fig. 6

Relationship between alcohol dehydrogenase 1B polymorphisms and oesophageal cancer risk in Japanese with inactive aldehyde dehydrogenase 2

Fig. 7

Relationship between alcohol dehydrogenase 1B polymorphisms and oesophageal cancer risk in Japanese people with active aldehyde dehydrogenase 2

ADH1B: alcohol dehydrogenase 1B; CI: confidence interval; RR: relative risk.

ADH1B: alcohol dehydrogenase 1B; CI: confidence interval; RR: relative risk.

Note: ADH1B*1/*1 corresponds to the slow-acting form of the enzyme and ADH1B*1/*2 and ADH1B*2/*2 corresponds to the fast-acting form.

Using our calculated risk relations for alcohol-attributable oesophageal cancer results in almost twofold higher estimates for deaths (5279) and DALYs lost (102 988) compared with the current GBD estimates (2749 and 53 826, respectively; Table 3). These results are irrespective of whether the estimates were based on cohort studies or on case-control studies, in each case adjusted for population prevalence of genotypes.

Table 3

Estimated mortality and burden of disease for alcohol-attributable oesophageal cancer in Japan 2010

Estimate	Women			Men			Total
	No. of deaths	No. of DALYs		No. of deaths	No. of DALYs		No. of deaths	No. of DALYs
GBD 2010	202	3 089		2 547	50 737		2 749	53 826
Japanese cohort studies	346	5 498		4 925	97 284		5 271	102 782
Japanese adjusted case-control studies	346	5 514		4 933	97 474		5 279	102 988

DALYs: disability-adjusted life-years; GBD: Global Burden of Disease.

Discussion

For Japan, we estimated a twofold higher mortality and burden of disease using risk functions derived from Japanese populations compared with the 2010 GBD estimates, which are based on global risk functions. We obtained separate estimates based on independent methods – either Japanese cohort data or adjusted Japanese case-control studies – and these estimates were comparable. This strengthens our conclusion that the current GBD method underestimates Japanese oesophageal cancer outcomes. Since we took into consideration genetic polymorphisms commonly observed in the Japanese population, we would predict a similar degree of underestimation for alcohol-attributable oral, pharynx and larynx cancers in Japan.,, Furthermore, the burden of other alcohol-attributable cancers where acetaldehyde plays an important role might be underestimated.,

We found that the slow-acting ADH1B variant also increased the risk for oesophageal cancer, regardless of ALDH2 variant. However, the slow-acting variant is only present in 6% of the Japanese population, whereas 90% of Caucasians carry the variant. As we had restricted all our analyses to Japanese individuals, the potential protective effect of the fast-acting ADH1B*1/*2 or *2/*2 variants has been already included. Similarly, risk estimates from cohort studies should not be affected by the differential risk curves for ALDH2 and ADH1B variants and their combinations if the prevalence of each combination of polymorphisms is reflected in the sample.

The study has some limitations. First, any systematic review or meta-analysis is only as good as the literature it is based on. Although case-control studies initially showed high heterogeneity as measured by I values indicating potential bias, there was little heterogeneity after these studies were stratified by ALDH2 variants. Second, while the procedures to estimate alcohol-attributable fractions are standard,,, subsequent adjustments to survey results may bias consumption in either direction.– However, as the same method of triangulation of surveys and per capita estimation was applied to GBD and to national estimates, the comparison between these estimates should be valid. Finally, the estimates of attributable risk and burden of disease for heavy alcohol intake are based on few studies and thus may be biased. By including risk estimates of people with alcohol dependence, we attempted to minimize this bias.

While there may be some biases in our quantitative estimates of alcohol-attributable burden for oesophageal cancer, they still show that global estimates underestimate the burden in Japan. This will likely be true for GBD estimates for China and the Republic of Korea as well, where a considerable proportion of the population also carry the inactive ALDH2 allele, (34% and 29%, respectively). In populations with a high proportion of these polymorphisms, studies based on global dose response data are likely to underestimate many alcohol-attributable cancers.

Efforts should be made to estimate country-specific risks for diseases affected by genetic polymorphisms, especially in countries with higher proportions of such polymorphisms. The current standard of applying global risk functions to local exposure data should be replaced by country-specific risk functions whenever possible. Country-specific risk functions should also be applied for other risk factors than alcohol., This will allow for better estimation of the burdens caused by risk factors and consequently better informed policy measures.