BACKGROUND: Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. METHODS: Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. RESULTS: The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. CONCLUSIONS: Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

Department of Chronic Disease Epidemiology Yale School of Public Health New Haven CT USA

Department of Civil and Environmental Engineering Tufts University School of Engineering Medford MA USA

Department of Dental Ecology University of North Carolina Chapel Hill NC USA

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA for CCFR CORECT GECCO ILCCO PanScan and PanC4

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

Department of Medicine Baylor College of Medicine Waco TX USA

Department of Oncology Johns Hopkins University School of Medicine Baltimore MD USA

Department of Periodontology Tufts University School of Dental Medicine Boston MA USA

Department of Public Health and Community Medicine Tufts University School of Medicine Boston MA USA

Department of the Molecular Biology of Cancer Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague Czech Republic

Division of Research Kaiser Permanente Northern California Oakland CA USA

Laboratory Medicine and Pathology The Colon Cancer Family Registry at Mayo Clinic Rochester MN USA

National Cancer Institute Rockville MD USA

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD USA

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