Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

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

doi:10.1186/s12916-020-01703-w

Abstract

BackgroundBilirubin, 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.MethodsIn 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.ResultsThe 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 main UGT1A1 SNP (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).ConclusionsAdditional 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.

Highlights

Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive
We further found that bilirubin levels predicted by instrumental variables excluding the Uridine diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) Single-nucleotide polymorphism (SNP) were suggestive of an inverse association with colorectal cancer (CRC) in men, which is in line with our initial hypothesis, but not in women
In conclusion, we observed that higher circulating bilirubin levels were positively associated with CRC risk in men

Summary

Introduction

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). CRC is more frequent in men than in women, and its burden is expected to increase by 60% to more than 2.2 million new cancer cases and 1.1 million cancer deaths by 2030 [2]. A compelling body of evidence from experimental and clinical studies has demonstrated that serum bilirubin, a byproduct of hemoglobin breakdown, has substantial anti-inflammatory and antioxidative properties [5,6,7,8,9]. UCB is the most active anti-oxidant part of total bilirubin [11,12,13]. The liver selectively removes UCB from the blood, and UCB is conjugated by a uridine diphosphoglucuronyltransferase (UGT1A1), after which it is transported to the bowel via the bile, where it is unconjugated by bacteria and excreted in the stool or reabsorbed [5,6,7,8,9]

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Conclusion