Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis

Abstract

Background Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). Methods We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. Results No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96–1.03, P value = 0.90) with CRC was shown. Conclusions Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.

Correlation between pre-treatment serum total blood bilirubin and unconjugated bilirubin and prognosis in patients with colorectal cancer

“…Studies have reported inconsistent results regarding the relationship between circulating bilirubin levels and risk of CRC. In a Mendelian randomization study (67878 cases), TBIL levels were not associated with the risk of CRC[ 11 ], which was similar to the findings of a meta-analysis and a prospective survey[ 12 , 13 ]. In an approximately 10-year follow-up study by He et al [ 14 ], baseline TBIL levels were found to be negatively correlated with the risk of CRC.…”

Associations between potential causal factors and colorectal cancer risk: A systematic review and meta‐analysis of Mendelian randomization studies

“…The sample size of exposure and outcome ranged between 1475 and 898 130 and between 1475 and 706 031, respectively (Table S3). The causal factors can be classified into eight categories: anthropometric characteristics and obesity‐related biomarkers ( n = 31), 7–16 lifestyle habits ( n = 15), 9,10,17–21 blood micronutrients ( n = 36), 10,22–31 blood fatty acids (FAs) and lipids ( n = 43), 10,24,32–37 inflammatory biomarkers ( n = 14), 10,38–42 pathological conditions and related biomarkers ( n = 30), 10,43–50 reproductive factors ( n = 12), 10,51,52 and other biomarkers ( n = 9) 10,53–57 (Table 1, Figure 2).…”

“…three studies 46,47 but not in another, 10 and the largest one reported an OR (95% CI) of 1.11 (1.01-1.22). 47 Furthermore, no associations were found for a homeostatic model assessment for beta-cell function (HOMA-B), 45 homeostatic model assessment for insulin resistance (HOMA-IR), 48 glycosylated hemoglobin A1c (HbA1c), 45 HbA, 10 fasting glucose, 10,43,45,48 fasting insulin, 43,48 fasting proinsulin, 10 gallstone disease, 49 and bilirubin 49,50 (Table 1, Figures 2 and 3, Figure S6).…”

Colorectal Cancer Study of Austria (CORSA): A Population-Based Multicenter Study

“…So far, CORSA contributed to multiple international consortia such as Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], COlorectal cancer GENeTics (COGENT) and COnsortium of METabolomics Studies (COMETS) [ 13 ]. Furthermore, CORSA was a partner in two ERANET-TRANSCAN-funded projects: MetaboCCC [ 11 , 12 , 44 , 45 , 46 , 50 , 51 ], and “Biomarkers related to folate-dependent metabolism in colorectal cancer recurrence and survival” (FOCUS) [ 35 , 36 ]. These interdisciplinary projects bring together multiple European CRC cohorts, including CORSA, the ColoCare study of the German Cancer Research Center in Heidelberg [ 14 ], the EnCoRe study of Maastricht University, the Netherlands [ 15 ], as well as the COLON study of Wageningen University, the Netherlands [ 16 ].…”