| Risk modification of colorectal adenoma by CYP7A1 polymorphisms and the role of bile acid metabolism in carcinogenesis. | |
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MedLine Citation:
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PMID: 22058145 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 G(rs8192871) 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 (C(rs10957057)C(rs8192879)G(rs8192877)T(rs11786580)A(rs8192871)G(rs13251096)) 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. |
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Authors:
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Betsy C Wertheim; Jeffrey W Smith; Changming Fang; David S Alberts; M Peter Lance; Patricia Thompson |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-4 |
Journal Detail:
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Title: Cancer prevention research (Philadelphia, Pa.) Volume: - ISSN: 1940-6215 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-7 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101479409 Medline TA: Cancer Prev Res (Phila) Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1Arizona Cancer Center, University of Arizona. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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