In this large consortial analysis, we report strong linear relationships between increasing BMI and the risk of OA. There was no evidence of effect modification when stratified by GERD symptoms, which may suggest an indirect proinflammatory route of association between BMI and OA/OGJA exists, as well as direct mechanical effects of android fat. There was putative evidence that gender may modify the relationship between BMI and OA in individuals without a history of GERD symptoms, which also may be interpreted as further evidence for an indirect proinflammatory route of association emanating from highly metabolic visceral fat when direct inflammatory routes (GERD) of pathogenesis do not predominate. Lastly, we found evidence for synergistic effects of BMI and GERD; the risk of cancer in obese individuals with GERD was significantly higher than predicted under an additive model.
Our findings of a strong positive dose–response relationship between BMI and the risk of OA reiterate the fact that this cancer is the primary malignancy associated with obesity.46
We also found similar, although somewhat weaker, associations for OGJA, and this is consistent with the hypothesis that OGJA represents a heterogeneous set of tumours with less clear origin compared with OA.47
Our results are compatible with findings from a previous meta-analysis that used published ORs from 14 studies,48
6 of them included here,15,18,26,33,34,49
as well as findings reported by other studies not included in the present analysis.50–56
Importantly, our study extends these results through the use of pooled individual participant data and harmonized variables and statistical models while also enabling analyses of effect modification and interaction. Overall, our findings support the hypothesis that BMI is a risk factor for OA and OGJA, the predominant causal theory of which is that obesity increases abdominal pressure, which subsequently relaxes the lower oesophageal sphincter, exposing the lower oesophagus to gastric acid and increasing the risk of GERD.20,48,56–58
In support of this hypothesis, the prevalence of GERD has been shown to increase with increasing levels of BMI.8,12
The large size of this analysis presented us the unique opportunity to investigate potential mechanisms of these associations. When stratified by history of GERD symptoms, we found no difference in the pattern of associations between BMI and these adenocarcinomas. In addition, adjustment for GERD symptoms (ever/never) did not attenuate the ORs for associations between BMI and OA/OGJA. These observations do not dispute the idea that a mechanical effect of BMI that increases the propensity for GERD and thus the risk for cancer exists, as we did not adjust for severity or frequency of GERD symptoms. Moreover, we could not adjust for asymptomatic GERD, as ascertainment of such would obviously have required all individuals to have undergone ambulatory 24-h pH-metry. However, what it may suggest is that an indirect, possibly proinflammatory, carcinogenic pathway between BMI and OA risk may exist, in addition to the accepted mechanical pathway of oesophageal sphincter distortion, increased intra-gastric pressure and increased risk of hiatal hernia. Spline models stratified by GERD and gender provided further evidence for an indirect proinflammatory pathogenic mechanism of BMI on OA risk—in individuals without a history of GERD symptoms, increasing BMI was associated with OA risk in men but not women. This may suggest that when inflammatory routes of associations are not saturated by the direct effects of GERD, the indirect effect can be detected. Such may be detectable in men, but not women, given the fact that android fat patterning, with highly metabolic visceral adipose tissue,20
is common in men relative to the preferred gynoid fat patterning, with a much lower metabolic rate, of women.21,22
Obesity-related hormones may induce oesophageal inflammatory damage, promoting proliferation and malignant transformation.24,59,60
Although we lack central adiposity metrics to test the theory directly, the evidence we present is provocative. However, our findings do not preclude the possibility of collider-stratification bias61
resulting from the more complex and possibly less direct relationships among obesity, GERD and OA/OGJA. This could occur if the relationship between GERD and BMI is mediated by a higher BMI giving way to increased severity and/or duration of GERD, in addition to the previously posited metabolic carcinogenic effects that a higher BMI may confer.8,12,14,20,24,30,57–66
In addition, it should be noted that our findings contrast with those of at least four previous studies15,19,56,67
that found stronger associations between BMI and OA/OGJA in individuals with a history of GERD symptoms, with the magnitude of the association increasing with increasing duration and severity of symptoms.67
However, these studies, some of which are included in the current analyses, suffered small sample sizes, raising the possibility that inconsistent findings could be attributed, at least in part, to unstable risk estimates. Lastly, and supporting the idea of direct mechanical (distortion of the lower oesophageal sphincter, increased intra-gastric pressure, increased risk of herniation) and indirect metabolic effects on OA risk, was the observation of synergism between BMI and GERD symptoms, with an excess risk attributable to synergistic interaction of 0.64 (0.12–1.17). Such interaction was previously suggested in a paper by Whiteman et al.
in an analysis of one of the studies included in this pooled analysis presented herein.19
As a whole, the evidence we present advocates for at least two pathways through which increased BMI can modify OA risk, which may also be related to the large gender disparity of these malignancies,6
given gender differences in adipose patterning. Although the stratified models suggest that the BMI–OA/OGJA relationships may vary by gender in some BMI categories, with stronger estimates observed in overweight and obese men, relative to equivalent estimates in women, it is important to keep in mind that, even in this large consortial analysis, the number of women available for analysis was limited. These limitations are also applicable to a previous meta-analysis48
and three other published studies68–70
that have made similar observations of differences by gender.6,20–22
Several limitations of this study should be considered when interpreting our findings. First, none of the studies included in these analyses collected data on fat distribution, including body shape, and few collected waist circumference at different ages during adulthood. Consequently, fat distribution could not be evaluated in our analyses. Future studies should identify and use improved measures of central obesity and other measures of the body habitus, including those that could be retrospectively documented.21,71
We have proposed that one of many ways this could be achieved is by retrospectively querying study participants about life-course changes in clothing sizes, particularly trouser waist size, at least for men, focusing on changes in adulthood.21
Results from two of three studies that evaluated waist circumference and BMI in relation to OA19,26,72
suggest that central obesity is a risk factor for OA, and a study of Barrett’s oesophagus, an OA precursor, suggests visceral fat may influence risk independent of BMI.73
A second potential limitation of our study is that the study-specific analyses are not adjusted for dietary intake, primarily because of differing ways these data were collected across studies. However, strong associations between BMI and OA/OGJA have been reported, regardless of whether adjustments are made for dietary intake.15,74
A third limitation is that our pooled analysis predominantly consists of case–control studies that lack the ability to determine the sequence of events between obesity and OA/OGJA, as BMI ascertainment among these studies was limited to ≥1 years before interview. However, restricting our analyses to individuals with a BMI >18.5 did not alter our findings. Moreover, the association between BMI and OA/OGJA was also found in the two prospective cohort studies. Furthermore, such differential recall in case–control studies would attenuate the magnitude of the risk for the association between BMI and OA/OGJA, thus assuaging any concerns that our findings are due to underestimates of past body weight in patients. Also related to the timing of case ascertainment relative to cancer onset is the potential limitation that data for this pooled analysis include case accrual over a 25-year period (1964–2006), during which time there have been rapid increases in the prevalence of obesity in all countries from which the included studies derive. However, we found no evidence of effects by calendar period, by visual inspection of forest plots and meta-regression of mid-year of recruitment.
In summary, this consortial analysis of pooled individual participant data has provided evidence that increasing BMI is associated with an increasing risk of OA and OGJA, and that these relationships are similar in those with and without a history of GERD symptoms. In addition, we provide tentative evidence for effect modification by gender in those without GERD symptoms and, lastly, evidence of synergistic interactions between BMI and GERD. Future studies should focus on elucidating the mechanisms that underlie these observations, specifically the multifaceted effects of obesity on the risk of OA.