title: Plasma choline metabolites and colorectal cancer risk in the Women's Health Initiative Observational Study.
abstract: Few studies have examined associations between plasma choline metabolites and risk of colorectal cancer. Therefore, we investigated associations between plasma biomarkers of choline metabolism [choline, betaine, dimethylglycine, and trimethylamine N-oxide (TMAO)] and colorectal cancer risk among postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. We selected 835 matched case-control pairs, and cases were further stratified by tumor site (proximal, distal, or rectal) and stage (local/regional or metastatic). Colorectal cancer was assessed by self-report and confirmed by medical records over the mean of 5.2 years of follow-up. Baseline plasma choline metabolites were measured by LC/MS-MS. In multivariable-adjusted conditional logistic regression models, plasma choline tended to be positively associated with rectal cancer risk [OR (95% confidence interval, CI)(highest vs. lowest quartile) = 2.44 (0.93-6.40); P trend = 0.08], whereas plasma betaine was inversely associated with colorectal cancer overall [0.68 (0.47-0.99); P trend = 0.01] and with local/regional tumors [0.64 (0.42-0.99); P trend = 0.009]. Notably, the plasma betaine:choline ratio was inversely associated with colorectal cancer overall [0.56 (0.39-0.82); P trend = 0.004] as well as with proximal [0.66 (0.41-1.06); P trend = 0.049], rectal [0.27 (0.10-0.78); P trend = 0.02], and local/regional [0.50 (0.33-0.76); P trend = 0.001] tumors. Finally, plasma TMAO, an oxidative derivative of choline produced by intestinal bacteria, was positively associated with rectal cancer [3.38 (1.25-9.16); P trend = 0.02] and with overall colorectal cancer risk among women with lower (vs. higher) plasma vitamin B12 levels (P interaction = 0.003). Collectively, these data suggest that alterations in choline metabolism, which may arise early in disease development, may be associated with higher risk of colorectal cancer. The positive association between plasma TMAO and colorectal cancer risk is consistent with an involvement of the gut microbiome in colorectal cancer pathogenesis.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York.
authors.forename: Sajin
authors.initials: S
authors.lastname: Bae
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington. German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany. Huntsman Cancer Institute, Salt Lake City, Utah. mac379@cornell.edu neli.ulrich@hci.utah.edu.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Neuhouser
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York.
authors.forename: Olga
authors.initials: O
authors.lastname: Malysheva
authors.affiliation: Department of Foods and Nutrition, University of Georgia, Athens, Georgia.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Bailey
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Liren
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Elissa C
authors.initials: EC
authors.lastname: Brown
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Cushing-Haugen
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ting-Yuan David
authors.initials: TY
authors.lastname: Cheng
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey. Department of Medical Pathology and Laboratory Medicine, University of California, Davis, California.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Miller
authors.affiliation: Department of Medical Pathology and Laboratory Medicine, University of California, Davis, California.
authors.forename: Ralph
authors.initials: R
authors.lastname: Green
authors.affiliation: Department of Preventive Medicine, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Dorothy S
authors.initials: DS
authors.lastname: Lane
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Shirley A A
authors.initials: SA
authors.lastname: Beresford
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York. mac379@cornell.edu neli.ulrich@hci.utah.edu.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Caudill
mesh_terms: D000368:Aged; D001622:Betaine / Q000097:blood; D002794:Choline / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000453:epidemiology* / Q000473:pathology; D005260:Female; D006801:Humans; D008744:Methylamines / Q000097:blood; D008875:Middle Aged; D012307:Risk Factors; D016387:Women's Health
chemical_list: D008744:Methylamines; D001622:Betaine; C005855:trimethyloxamine; D002794:Choline