Risk Modification of Colorectal Adenoma byCYP7A1Polymorphisms and the Role of Bile Acid Metabolism in Carcinogenesis

Abstract

Cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids, is a postulated gene modifier of colorectal cancer risk and target for the therapeutic bile acid, ursodeoxycholic acid (UDCA). We investigated associations between CYP7A1 polymorphisms and fecal bile acids, colorectal adenoma (CRA), and UDCA efficacy for CRA prevention. Seven tagging, single-nucleotide polymorphisms (SNPs) in CYP7A1 were measured in 703 (355 UDCA, 348 placebo) participants of a phase III chemoprevention trial, of which 495 had known baseline fecal bile acid concentrations. In the placebo arm, participants with two minor Grs8192871 alleles (tag for a low-activity promoter polymorphism at -204) had lower odds of high secondary bile acids (OR, 0.26; 95% CI, 0.10–0.69), and CRA at 3 years' follow-up (OR, 0.41; 95% CI, 0.19–0.89), than AA carriers. Haplotype construction from the six polymorphic SNPs showed participants with the third-most common haplotype (Crs10957057Crs8192879Grs8192877Trs11786580Ars8192871Grs13251096) had higher odds of high primary bile acids (OR, 2.34; 95% CI, 1.12–4.89) and CRA (OR, 1.89; 95% CI, 1.00–3.57) than those with the most common CTACAG haplotype. Furthermore, three SNPs (rs8192877, rs8192871, and rs13251096) each modified UDCA efficacy for CRA prevention, and CCGTAG-haplotype carriers experienced 71% lower odds of CRA recurrence with UDCA treatment, an effect not present for other haplotypes (test for UDCA-by-haplotype interaction, P=0.020). Our findings support CYP7A1 polymorphisms as determinants of fecal bile acids and risk factors for CRA. Further, UDCA efficacy for CRA prevention may be modified by genetic variation in CYP7A1, limiting treatment benefit to a subgroup of the population.

Effect of Ursodeoxycholic Acid Use on the Risk of Colorectal Neoplasia in Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Disease

“…UDCA efficacy for sporadic adenoma prevention may be modified by genetic variation in CYP7A1, the rate-limiting cholesterol 7a-hydroxylase enzyme that catalyzes the initial step in hepatic bile acid synthesis. 55 Thompson et al 56 also reported a significant influence of sex on the effects of UDCA in a phase III randomized, doubleblind placebo-controlled trial of low-dose UDCA. Although UD-CA was associated with a 36% risk reduction in developing advanced lesions (CRC, HGD, villous or tubulovillous histology, or large [$1 cm] size) among men, there was a 3-fold increase in the risk of advanced lesions with UDCA use among women, particularly obese women younger than 65 years with high dietary fat intake.…”

Association between Circulating Vitamin D Metabolites and Fecal Bile Acid Concentrations

“…Analysis of fecal bile acid levels for the UDCA trial was completed in conjunction with the parent clinical trial and has been described in detail elsewhere(6, 13). Briefly, at baseline, study participants provided 72-hour stool samples that were frozen and shipped overnight on dry ice to the University of Arizona Cancer Center(13).…”

“…Briefly, at baseline, study participants provided 72-hour stool samples that were frozen and shipped overnight on dry ice to the University of Arizona Cancer Center(13). Samples were then homogenized with an equal weight of water for 15 minutes and centrifuged(13). Fecal water was comprised of the aqueous phase after centrifugation and was stored at −80°C.…”

“…Measurement of bile acids was conducted using gas chromatography(6, 20). Results were obtained for lithocholic acid (LCA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), cholic acid (CA), ursodeoxycholic acid (UDCA), ursocholic acid (UC), and other bile acids, a category that included isodeoxycholic, isoursodeoxycholic, 7-ketolithocholic, and 12-ketolithocholic acids(6, 13). Concentrations of total primary bile acids were calculated by summing the values for CDCA and CA, while total secondary bile acid concentration was assessed by combining the remaining values.…”

“…Further analyses of the same trial revealed that there were sex differences in response to UDCA treatment, with men, but not women, who received UDCA having a significantly reduced risk of developing advanced lesions(12). Effect modification of UDCA treatment by genetic variation in cholesterol 7α-hydroxylase ( CYP7A1) , the expression of which is controlled primarily by the farnesoid X receptor (FXR) and liver X receptor (LXR), was also reported(13). …”