Background: Secondary bile acids, specifically deoxycholic acid (DCA), are probable carcinogens of colorectal cancer, particularly for lesions arising in the proximal colon. Cholesterol 7α‐hydroxylase (CYP7A1) is the rate‐limiting enzyme in the conversion of cholesterol to primary bile acids in the liver. Genetic variation in CYP7A1 has been reported to modify risk of colorectal neopolasia arising in the proximal colon.
Methods: Using the placebo arm of our ursodeoxycholic acid chemoprevention trial, we studied the relationships between baseline fecal bile acid concentrations, six allelic variants in CYP7A1, and risk of proximal adenomas after three years of follow‐up (n = 253). Because bile acid levels are strongly influenced by sex, we considered gender as a potential effect modifier. After testing four possible modes of inheritance for associations between genetic polymorphisms and proximal adenoma, we present results generated under log‐additive models.
Results: The relationship between fecal DCA levels and development of proximal adenoma was strongly modified by gender (pinteraction < 0.001). Compared with the lowest quintile, higher levels of DCA were associated with significantly increased odds of proximal adenoma in men (OR = 7.14; 95% CI = 2.07 to 24.6) but non‐significantly decreased odds in women (OR = 0.39, 95% CI = 0.13 to 1.20). These associations were slightly attenuated for men (OR = 5.82; 95% CI = 1.65 to 20.5) and women (OR = 0.44, 95% CI = 0.14 to 0.43) after adjusting for age and body mass index. In addition, analyses of two linked CYP7A1 SNPs (D′ = 0.75 and r2 = 0.5) showed that carriage of the minor allele for rs8192871 and rs13251096 lowered the odds of proximal adenoma by 45% (OR = 0.55; 95% CI = 0.36 to 0.85) and 41% (OR = 0.59, 95% CI = 0.40 to 0.89), respectively. Furthermore, these two SNPs were associated with DCA, such that carriers of two minor alleles had significantly lower fecal DCA levels (Kruskal‐Wallis p = 0.003 for both SNPs). None of the other four CYP7A1 SNPs showed any association with proximal adenoma or fecal bile acid levels.
Conclusions: In this study population, CYP7A1 polymorphisms are significantly associated with risk of adenoma in the proximal colon, likely through their effects on bile acid levels. Sex, age, body mass index, and other factors that influence bile acid levels may further affect this risk.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A121.