TY - JOUR
T1 - Circulating bilirubin levels and risk of colorectal cancer: 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 - EPIC cohort study
PY - 2020/9/3
Y1 - 2020/9/3
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.
U2 - 10.1186/s12916-020-01703-w
DO - 10.1186/s12916-020-01703-w
M3 - Article
C2 - 32878631
SN - 1741-7015
VL - 18
JO - BMC Medicine
JF - BMC Medicine
IS - 1
ER -
