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An Association between Genetic Polymorphisms in the Ileal Sodium-dependent Bile Acid Transporter Gene and the Risk of Colorectal Adenomas¹

Department of Preventive Medicine [W. W., S. X., S. A. I., Q. C., A. T. D., R. W. H.] and Department of Medicine [A. S.], University of Southern California/Norris Cancer Center, Los Angeles, California 94587

Epidemiological and experimental studies have implicated bile acids (particularly secondary bile acids) as important factors in the development of colorectal cancer. The ileal sodium-dependent bile acid transporter (ISBT) is a crucial player in the enterohepatic circulation of bile acids. Genetic defects in ISBT may result in malabsorption of bile acids and a loss of bile acids into the large intestine, with a resultant increase in the cytotoxic secondary bile acids in the colon. In a case-control study, we investigated the association between two sequence variations in SLC10A2, the gene encoding ISBT, and colorectal adenomas, a precursor lesion of colorectal cancer. The frequency of the missense mutation in codon 171 of exon 3 (a nucleotide transversion from G to T resulting in an alanine to serine substitution) was not significantly different between cases and controls. However, we found a 2-fold higher risk of colorectal adenomas associated with a CT nucleotide transition in codon 169 of exon 3 (odds ratio = 2.06; 95% confidence interval: 1.10–3.83). Logistic regression analysis using A171S/169 CT haplotypes as the allelic markers showed that among AA wild-type homozygotes for A171S mutation, this CT nucleotide transition in codon 169 was associated with a 2.42 times increased risk (odds ratio = 2.42; 95% confidence interval: 1.26–4.63). This initial observation of an association between a polymorphism in the SLC10A2 gene and the risk of colorectal adenomatous polyps would, if confirmed by other studies, support the role of bile acids in the carcinogenesis of colorectal cancer.

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