Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, California.
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
- Division of Biomedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
- Division of Gastroenterology, Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
- Colorectal Oncogenomic Group, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.
- Prevention and Cancer Control, Clinical Institutes and Quality Programs, Ontario Health (Cancer Care Ontario), Toronto, Ontario, Canada.
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
BACKGROUND: Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits.
METHODS: We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer.
RESULTS: We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91-0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis.
CONCLUSIONS: Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk.
IMPACT: Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk.
- 2014-0244: Colorectal Tumor Risk Prediction in the PLCO Trial (ULRIKE PETERS)