Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium

Abstract

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m² ); normal (18.5-22.9 kg/m² ); overweight (23-24.9 kg/m² ); and obese (25+ kg/m² ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Keywords: Asia Cohort Consortium; biliary tract cancer; body mass index; obesity; pooled analysis.

Figure 1.

Causal diagram of BMI, cholelithiasis, and biliary tract cancer. The total effect between BMI and biliary tract cancer can be decomposed into four components: a pure indirect effect (①②); a mediated interaction effect (①③⑤); a reference interaction effect (④⑤); and a controlled direct effect (⑥). A direct effect was defined as a combination of the controlled direct effect and the reference interaction effect. An indirect effect was defined as a combination of the mediation interaction effect and the pure indirect effect.