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Plasma Choline Metabolites and Colorectal Cancer Risk in the Women's Health Initiative Observational Study
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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. Cancer Res; 74(24); 7442–52. ©2014 AACR.
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In the citing paper
“Recent human studies have established that the levels of TMAO in serum are positively correlated with impaired renal function, colorectal cancer, and cardiovascular disease (CVD) (8, 10, 17, 18).”
From Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine- N -Oxide (2015) · cites this paper as [18]
Experimental — accuracy not yet measuredIn the citing paper
“In support of this hypothesis, the association between plasma level of TMAO and risk of CRC was restricted to patients with low plasma levels of vitamin B12.151”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [151]
In the citing paper
“Some,147, 148 but not all,149–151 prospective studies have associated higher dietary and plasma levels of choline with increased risk of colorectal neoplasia.”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [151]
In the citing paper
“The Women's Health Initiative and the alpha-tocopherol, beta-carotene cancer prevention observational studies reported that alterations in choline metabolism and plasma TMAO concentrations were predicted risk factors for colorectal cancer (7,83).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [7]
In the citing paper
“Recent human studies have established that the levels of TMAO in serum are positively correlated with impaired renal function, colorectal cancer, and cardiovascular disease (CVD) (8, 10, 17, 18).”
From Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine- N -Oxide (2015) · cites this paper as [18]
In the citing paper
“Recent human studies have established that the levels of TMAO in serum are positively correlated with impaired renal function, colorectal cancer, and cardiovascular disease (CVD) (8, 10, 17, 18).”
From Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine- N -Oxide (2015) · cites this paper as [18]
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Metadata
- Authors
- Bae, S., Ulrich, C. M., Neuhouser, M. L., Malysheva, O., Bailey, L. B., Xiao, L., Brown, E. C., Cushing-Haugen, K. L., Zheng, Y., Cheng, T.-Y. D., Miller, J. W., Green, R., Lane, D. S., Beresford, S. A. A., & Caudill, M. A.
- Affiliations
- Cornell University (US)
- German Cancer Research Center (DE)
- Fred Hutch Cancer Center (US)
- University of Georgia (US)
- 2Fred Hutchinson Cancer Research Center, Seattle, Washington.
- Rutgers, The State University of New Jersey (US)
- University of California, Davis (US)
- Stony Brook School (US)
- Corresponding author
- Ulrich, Cornelia M.
- Caudill, Marie A.
- ORCID
- Venue
- Cancer Research
- Published
- 2014-12-14
- Volume
- 74
- Issue
- 24
- Pages
- 7442-7452
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4268282
- OpenAlex
- W2092436074
- Cited by
- 253
- References
- 56
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 27 · 2023: 34 · 2022: 23 · 2021: 34 · 2020: 24 · 2019: 20 · 2018: 19 · 2017: 17 · 2016: 16 · 2015: 13
- FWCI
- 15.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Institutes of Health (HHSN268201100004C, n01wh22110-38-0-0, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, N01 WH022110)
- National Institute on Aging (HHSN-271-2011-00004C,)
- National Heart, Lung, and Blood Institute (HHSN2682011-00001I, HHSN2682011-00002I, HHSN2682011‐00004I, HHSN268201100046C, HHSN2682011-00003I)
- National Cancer Institute (R01CA120523)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- colorectal cancer risk, choline metabolism, plasma choline, betaine, dimethylglycine, trimethylamine N-oxide, rectal cancer, postmenopausal women, vitamin B12, tumor location, tumor stage, plasma biomarkers, Women's Health Initiative Observational Study, gut microbiota, oxidative stress, inflammation
- MeSH terms
- Aged, Betaine, Choline, Female, Humans, Methylamines, Middle Aged, Risk Factors, Colorectal Neoplasms, Women's Health
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