Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses
Authors: Seyed Khoei Nazlisadat , Jenab Mazda , Murphy Neil , Banbury Barbara L. , Carreras-Torres Robert , Viallon Vivian , Kühn Tilman , Bueno-de-Mesquita Bas , Aleksandrova Krasimira , Cross Amanda J. , Weiderpass Elisabete , Stepien Magdalena , Bulmer Andrew , Tjønneland Anne , Boutron-Ruault Marie-Christine , Severi Gianluca , Carbonnel Franck , Katzke Verena , Boeing Heiner , Bergmann Manuela M. , Trichopoulou Antonia , Karakatsani Anna , Martimianaki Georgia , Palli Domenico , Tagliabue Giovanna , Panico Salvatore , Tumino Rosario , Sacerdote Carlotta , Skeie Guri , Merino Susana , Bonet Catalina , Rodríguez-Barranco Miguel , Gil Leire , Chirlaque Maria-Dolores , Ardanaz Eva , Myte Robin , Hultdin Johan , Perez-Cornago Aurora , Aune Dagfinn , Tsilidis Konstantinos K. , Albanes Demetrius , Baron John A. , Berndt Sonja I. , Bézieau Stéphane , Brenner Hermann , Campbell Peter T. , Casey Graham , Chan Andrew T. , Chang-Claude Jenny , Chanock Stephen J. , Cotterchio Michelle , Gallinger Steven , Gruber Stephen B. , Haile Robert W. , Hampe Jochen , Hoffmeister Michael , Hopper John L. , Hsu Li , Huyghe Jeroen R. , Jenkins Mark A. , Joshi Amit D. , Kampman Ellen , Larsson Susanna C. , Le Marchand Loic , Li Christopher I. , Li Li , Lindblom Annika , Lindor Noralane M. , Martín Vicente , Moreno Victor , Newcomb Polly A. , Offit Kenneth , Ogino Shuji , Parfrey Patrick S. , Pharoah Paul D. P. , Rennert Gad , Sakoda Lori C. , Schafmayer Clemens , Schmit Stephanie L. , Schoen Robert E. , Slattery Martha L. , Thibodeau Stephen N. , Ulrich Cornelia M. , van Duijnhoven Franzel J. B. , Weigl Korbinian , Weinstein Stephanie J. , White Emily , Wolk Alicja , Woods Michael O. , Wu Anna H. , Zhang Xuehong , Ferrari Pietro , Anton Gabriele , Peters Annette , Peters Ulrike , Gunter Marc J. , Wagner Karl-Heinz , Freisling Heinz 
Published: September 2020

Background

Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.

Methods

In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10−8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.

Results

The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04–1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76–0.97)). In the MR analysis of the mainUGT1A1SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02–1.12);P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96–1.06);P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).

Conclusions

Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.