The cause of glioma, the most frequent type of primary malignant brain tumor, remains largely unknown [1
]. With the exception of genetic syndromes, ionizing radiation is the only well-established risk factor for glioma [1
]. Indeed, these unusual exposures could explain only a minority of exposed individuals, indicating that other factors like dietary, occupational exposures and other personal and residential exposures may play a critical role in the carcinogenesis of glioma [2
It is widely accepted that intake of alcoholic beverages is one of the most important lifestyle-related risk factor for human cancer after tobacco smoking [3
]. It has been estimated that in 2002, 3.6% of all cancers (5.2% in men, 1.7% in women) are attributable to alcohol consumption worldwide [3
]. A causal association has been confirmed between alcohol consumption and cancers of the oral cavity, pharynx, larynx, oesophagus, liver, colon, rectum, and female breast [5
]. However, whether a causal link between alcohol consumption and risk of glioma exists is still unclear. To clarify this issue, we therefore conducted a meta-analysis of published observational studies.
The association between alcohol consumption and risk of glioma has long been explored with conflicting results. The studies involved the questions about total alcohol consumption and a specific-type of alcoholic beverage. One previous meta-analysis of 19 studies has been conducted to quantitatively assesse the relationship between alcohol drinking and brain tumor [16
]. Galeone and colleagues found that alcohol consumption did not appear to be associated with brain cancer. In a dose-response analysis, a moderate increase in risk of brain tumor for intakes of two or more drinks per day [16
]. It is well known that brain tumors are a heterogeneous group of tumors which vary in tissue origins, invasive potential and prognosis. Thus, an analysis of combination of glioma and meningioma may be the result of some unknown bias and make these findings more confounding. In order to derive a more accurate estimation of the association between alcohol intake and glioma, an updated meta-analysis was performed. In our meta-analysis, those studies involving total brain tumors or meningioma were excluded [17
]. Thus, a final total of 19 studies were identified for our analysis. Our analyses indicated that the risk of glioma did not appear associated with alcohol intake.
In subgroup analysis by geographic area, a significant association was observed in North American studies, but this correlation did not emerge for European or Asian/Australian studies. When subgroup analyses were performed according to study design, no significant associations were observed in cohort or hospital-based case-control studies. However, in population-based case-control studies, an 18% decreased risk was detected among alcohol drinkers compared with nondrinkers. The significance of these findings is unclear. Therefore, additional studies are warranted to confirm these findings.
We also evaluated the correlation between risk of glioma and specific-types of alcoholic beverage. No associations emerged with beer, wine, or spirits. These findings were consistent with all studies except two [30
]. In a hospital-based case-control study, Burch and colleagues found that wine consumption was associated with an elevated risk of glioma (RR = 2.14, 95% CI = 1.28–3.60) [30
]. However, a lower risk (RR = 0.58, 95% CI = 0.38–0.91) was observed in a population-based case-control study with 110 cases and 417 controls [34
]. The two risk estimates were not adjusted for any confounders. Thus, residual confounding was possible. Furthermore, two studies have investigated several types of wine in relation to glioma [34
]. The study conducted by Ryan found a decreased risk for drinkers of white wine (RR = 0.53, 95% CI = 0.33–0.85) and red wine (RR = 0.33, 95% CI = 0.33–1.08), although this correlation for red wine was not statistically significant [34
]. In the latter study of Hurley, no meaningful associations were observed for white, red or fortified wine [36
A dose-response relationship in a meta-analysis supports to a suspected causal relationship between exposure and disease. Three studies have examined the relationship between risk of glioma and different levels of alcohol consumption [36
]. Two studies shown non-significant increase or decrease in risk emerged [36
]. However, in the Melbourne Collaborative cohort study, Baglietto and colleagues found an 16% increase risk for each additional 10 g/day and people drinking 40 g/day of alcohol or more had up to three-fold higher risk relative to nondrinkers [43
]. The discrepancy may be due to the limitations of statistical power and different levels of exposure defined in each study. To overcome these limitations, universal standards (moderate alcohol drinking was defined as consumption of <25 g/day of ethanol, and heavy as consumption of ≥25 g/day of ethanol) were adopted and the dose-risk analysis was performed. Our results still showed no significant association between risk of glioma and moderate or heavy intake of alcohol. However, significant heterogeneity was found (I2
= 63.3%). Moreover, only three studies were identified for dose-response analysis. Therefore, the relationship between glioma and alcohol drinking needs further discussion.
Although we found that alcohol consumption was not asssociated with glioma risk, various mechanisms have been proposed. First, alcohol is capable of traversing the blood-brain barrier and has been considered as an established factor for several other tumors or diseases [16
]. Therefore, alcohol could play a carcinogenic role in the brain directly. Second, acetaldehyde and reactive oxygen species, the products of alcohol metabolism, are toxic to cells when they react with proteins, lipids, and DNA [43
]. Moreover, acetaldehyde has been demonstrated to be a neurocarcinogen in animals [43
]. Finally, alcohol contains N
-nitroso compounds, which result in brain tumors in animals [36
Of note, several limitations should be addressed in our analysis. First, since our meta-analysis was based on observational studies, confounding factors are often of concern. As we performed an analysis limited to those studies that provided adjusted risk estimates, a 14% decreased risk of glioma was observed among alcohol drinkers. Thus, we cannot rule out the probability that our findings were due to confounding from other risk factors. Second, involving specific-type of alcohol drinking could result in an underestimation of the risk associated with the true amount of alcohol consumed. Third, we were unable to assess separately various types of glioma (e.g., astrocytoma, oligodendroglioma, glioblastoma, etc
.) because limited data were eligible. Fourth, a separate analysis for females and males was not possible since only two studies provided results separately for men and women. Epidemiological data have shown the incidence of glioma is 1.5–2 fold higher in men than in women [12
]. Fifth, most evidence was retrospective. Thus, the possible recall and selection bias may confound the relationship. Finally, potential publication bias may distort the association between alcohol consumption and risk of glioma.