TY - JOUR

T1 - Circulating bilirubin levels and risk of colorectal cancer

T2 - serological and Mendelian randomization analyses

AU - Seyed Khoei, Nazlisadat

AU - Jenab, Mazda

AU - Murphy, Neil

AU - Banbury, Barbara L.

AU - Carreras-Torres, Robert

AU - Viallon, Vivian

AU - Kühn, Tilman

AU - Bueno-de-Mesquita, Bas

AU - Aleksandrova, Krasimira

AU - Cross, Amanda J.

AU - Weiderpass, Elisabete

AU - Stepien, Magdalena

AU - Bulmer, Andrew

AU - Tjønneland, Anne

AU - Boutron-Ruault, Marie Christine

AU - Severi, Gianluca

AU - Carbonnel, Franck

AU - Katzke, Verena

AU - Boeing, Heiner

AU - Bergmann, Manuela M.

AU - Trichopoulou, Antonia

AU - Karakatsani, Anna

AU - Martimianaki, Georgia

AU - Palli, Domenico

AU - Tagliabue, Giovanna

AU - Panico, Salvatore

AU - Tumino, Rosario

AU - Sacerdote, Carlotta

AU - Skeie, Guri

AU - Merino, Susana

AU - Bonet, Catalina

AU - Rodríguez-Barranco, Miguel

AU - Gil, Leire

AU - Chirlaque, Maria Dolores

AU - Ardanaz, Eva

AU - Myte, Robin

AU - Hultdin, Johan

AU - Perez-Cornago, Aurora

AU - Aune, Dagfinn

AU - Tsilidis, Konstantinos K.

AU - Albanes, Demetrius

AU - Baron, John A.

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

AU - Brenner, Hermann

AU - Campbell, Peter T.

AU - Casey, Graham

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Cotterchio, Michelle

AU - Gallinger, Steven

AU - Gruber, Stephen B.

AU - Haile, Robert W.

AU - Hampe, Jochen

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Hsu, Li

AU - Huyghe, Jeroen R.

AU - Jenkins, Mark A.

AU - Joshi, Amit D.

AU - Kampman, Ellen

AU - Larsson, Susanna C.

AU - Le Marchand, Loic

AU - Li, Christopher I.

AU - Li, Li

AU - Lindblom, Annika

AU - Lindor, Noralane M.

AU - Martín, Vicente

AU - Moreno, Victor

AU - Newcomb, Polly A.

AU - Offit, Kenneth

AU - Ogino, Shuji

AU - Parfrey, Patrick S.

AU - Pharoah, Paul D.P.

AU - Rennert, Gad

AU - Sakoda, Lori C.

AU - Schafmayer, Clemens

AU - Schmit, Stephanie L.

AU - Schoen, Robert E.

AU - Slattery, Martha L.

AU - Thibodeau, Stephen N.

AU - Ulrich, Cornelia M.

AU - van Duijnhoven, Franzel J.B.

AU - Weigl, Korbinian

AU - Weinstein, Stephanie J.

AU - White, Emily

AU - Wolk, Alicja

AU - Woods, Michael O.

AU - Wu, Anna H.

AU - Zhang, Xuehong

AU - Ferrari, Pietro

AU - Anton, Gabriele

AU - Peters, Annette

AU - Peters, Ulrike

AU - Gunter, Marc J.

AU - Wagner, Karl Heinz

AU - Freisling, Heinz

PY - 2020

Y1 - 2020

N2 - 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 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). 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.

AB - 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 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). 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.

KW - Anti-oxidants

KW - Bilirubin

KW - Cancer

KW - Colorectal cancer

KW - Mendelian randomization analysis

U2 - 10.1186/s12916-020-01703-w

DO - 10.1186/s12916-020-01703-w

M3 - Journal article

C2 - 32878631

AN - SCOPUS:85090261575

VL - 18

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

IS - 1

ER -