Association of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancer
Abstract
Heme oxygenase-1 (HMOX1) and bilirubin UDP-glucuronosyltransferase (UGT1A1) enzymes, both involved in bilirubin homeostasis, play an important role in the oxidative stress defense. The objective of our study was to assess the effect of promoter variations of HMOX1 and UGT1A1 genes and of serum bilirubin on the risk of sporadic colorectal cancer (CRC).
This exploratory case-control study was based on 777 CRC patients and 986 controls from the Czech Republic. The (GT)n and (TA)n dinucleotide variations in HMOX1 and UGT1A1 gene promoters, respectively, were determined by fragment analysis.
In addition, the A(-413)T variant in HMOX1 promoter was also analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Serum bilirubin levels were compared in a subset of 174 cases and 247 controls, for whom biochemical data were available.
After adjustment for age, a significant association between CRC risk and UGT1A1*28 allele carrier status was detected [odds ratio (95% confidence intervals) = 0.80 (0.600.97), p = 0.022]. No association between CRC risk and individual HMOX1 gene variants was observed, although a diplotype analysis revealed an increased risk for a specific HMOX1 genotype combination.
These effects were more pronounced in males. Substantially lower serum bilirubin levels were detected in CRC patients compared to the controls (p < 0.001); each 1 mu mol/L decrease in serum bilirubin was associated with a 7% increase of CRC risk (p < 0.001).
In conclusion, UGT1A1*28 allele carrier status might be a protective factor against the development of CRC in the male population, whereas low serum bilirubin levels are associated with an increased risk of CRC in both genders.