Association of Genetic Liability to Allergic Diseases with Overall and Early-Onset Colorectal Cancer Risk: A Mendelian Randomization Study

Saleh Alduhayh¹, Ruhina Shirin Laskar², Xia Jiang^{3

4

5}, Zhaozhong Zhu⁶, Emma E Vincent^{7

8

9}, Andrei-Emil Constantinescu^{7

8

9}, Daniel D Buchanan^{10

11

12}, Robert C Grant¹³, Amanda I Phipps^{14

15}, Hermann Brenner^{16

17}, Wen-Yi Huang¹⁸, Sun-Seog Kweon^{19

20}, Li Li²¹, Rachel Pearlman²², Sergi Castellví-Bel²³, Stephen B Gruber²⁴, Christopher I Li¹⁴, Andrew Pellatt²⁵, Elizabeth A Platz²⁶, Bethany Van Guelpen^{27

28}, Wei Zheng²⁹, Andrew T Chan³⁰, Jane C Figueiredo³¹, Shuji Ogino^{32

33

34

35}, Cornelia M Ulrich³⁶, Marc J Gunter^{37

38}, Philip Haycock^#^{7

8

9}, Gianluca Severi^#³⁹, Neil Murphy^#³⁷, Niki Dimou^#³⁷

Affiliations

¹ Public Health Department, College of Public Health, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
² Department of Oncology, Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom.
³ Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁴ Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁵ Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Solna, Sweden.
⁶ Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
⁷ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
⁸ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, United Kingdom.
⁹ School of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
¹⁰ Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia.
¹¹ University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, Australia.
¹² Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Australia.
¹³ Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
¹⁴ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington.
¹⁵ Department of Epidemiology, University of Washington, Seattle, Washington.
¹⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁷ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
¹⁹ Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.
²⁰ Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea.
²¹ Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
²² Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
²³ Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
²⁴ Center for Precision Medicine and Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California.
²⁵ Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
²⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
²⁷ Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden.
²⁸ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
²⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
³⁰ Massachusetts General Hospital, Clinical and Translational Epidemiology Unit, Boston, Massachusetts.
³¹ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
³² Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
³³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
³⁴ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
³⁵ Tokyo Medical and Dental University (Institute of Science Tokyo), Tokyo, Japan.
³⁶ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
³⁷ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
³⁸ Cancer Epidemiology and Prevention Research Unit, School of Public Health, Imperial College London, London, United Kingdom.
³⁹ Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Gustave Roussy, Inserm, U1018, Exposome, Heredity, Cancer, and Health Team, CESP, Villejuif, France.

^# Contributed equally.

PMID: 39982694
PMCID: PMC12046324
DOI: 10.1158/1055-9965.EPI-24-0970

Association of Genetic Liability to Allergic Diseases with Overall and Early-Onset Colorectal Cancer Risk: A Mendelian Randomization Study

Saleh Alduhayh et al. Cancer Epidemiol Biomarkers Prev. 2025.

. 2025 May 2;34(5):722-736.

doi: 10.1158/1055-9965.EPI-24-0970.

Authors

Affiliations

¹ Public Health Department, College of Public Health, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
² Department of Oncology, Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom.
³ Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁴ Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁵ Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Solna, Sweden.
⁶ Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
⁷ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
⁸ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, United Kingdom.
⁹ School of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
¹⁰ Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia.
¹¹ University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, Australia.
¹² Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Australia.
¹³ Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
¹⁴ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington.
¹⁵ Department of Epidemiology, University of Washington, Seattle, Washington.
¹⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁷ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
¹⁹ Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.
²⁰ Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea.
²¹ Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
²² Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
²³ Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
²⁴ Center for Precision Medicine and Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California.
²⁵ Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
²⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
²⁷ Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden.
²⁸ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
²⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
³⁰ Massachusetts General Hospital, Clinical and Translational Epidemiology Unit, Boston, Massachusetts.
³¹ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
³² Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
³³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
³⁴ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
³⁵ Tokyo Medical and Dental University (Institute of Science Tokyo), Tokyo, Japan.
³⁶ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
³⁷ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
³⁸ Cancer Epidemiology and Prevention Research Unit, School of Public Health, Imperial College London, London, United Kingdom.
³⁹ Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Gustave Roussy, Inserm, U1018, Exposome, Heredity, Cancer, and Health Team, CESP, Villejuif, France.

^# Contributed equally.

PMID: 39982694
PMCID: PMC12046324
DOI: 10.1158/1055-9965.EPI-24-0970

Abstract

Background: The tumor immunosurveillance theory supports that allergic conditions could decrease cancer risk. However, observational evidence yielded inconsistent results for the association between allergic diseases and colorectal cancer risk. We used Mendelian randomization (MR) to examine potential causal associations of allergies with the risk of overall and early-onset colorectal cancer.

Methods: Genome-wide association study summary statistical data were used to identify genetic variants associated with allergic diseases (Nvariants = 65) and individual allergic conditions (asthma, hay fever/allergic rhinitis, and eczema). Using two-sample MR, we examined these variants in relation to incident overall (Ncases = 52,775 cases) and early-onset colorectal cancer (Ncases = 6,176). The mediating role of white blood cells was examined using multivariable MR.

Results: In inverse-variance-weighted models, genetic liability to allergic diseases was inversely associated with overall {OR per log (odds) = 0.90 [95% confidence interval (CI), 0.85-0.96]; P < 0.01} and early-onset colorectal cancer [OR = 0.83 (95% CI, 0.73-0.95); P = 0.01]. Similar inverse associations were found for hay fever/allergic rhinitis or eczema, whereas no evidence of association was found between liability to asthma-related phenotypes and colorectal cancer risk. Multivariable MR adjustment for eosinophils weakened the inverse associations for liability to allergic diseases for overall [OR = 0.96 (95% CI, 0.89-1.03); P = 0.26] and early-onset colorectal cancer [OR = 0.86 (95% CI, 0.73-1.01); P = 0.06].

Conclusions: Our study supports a potential causal association between liability to allergic diseases, specifically hay fever/allergic rhinitis or eczema, and colorectal cancer, possibly at least in part mediated via eosinophil counts.

Impact: Our results provide evidence that allergic responses may also have a role in immunosurveillance against colorectal cancer.

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Conflict of interest statement

R.C. Grant reports personal fees from AstraZeneca, Eisai, Incyte, Knight Therapeutics, Guardant Health, and Ipsen outside the submitted work. L. Li reports grants from the NIH during the conduct of the study. R. Pearlman reports grants from Pelotonia, other support from Myriad Genetics, and grants from the NCI during the conduct of the study. S.B. Gruber reports grants from the NIH during the conduct of the study, as well as other support from Brogent International LLC, AbbVie, Invitae, and Halo Dx outside the submitted work. E.A. Platz (elected member of the AACR Board of Directors) reports personal fees from the American Association for Cancer Research outside the submitted work. B. Van Guelpen reports grants from the Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lions Cancer Research Foundation, and Insamlingsstiftelsen, Umeå University during the conduct of the study, as well as personal fees from AstraZeneca AB outside the submitted work. A.T. Chan reports personal fees from Boehringer Ingelheim and Pfizer and grants from Freenome outside the submitted work. S. Ogino reports grants from the NIH and the American Cancer Society during the conduct of the study. C.M. Ulrich reports grants from the NIH during the conduct of the study; in addition, she has, as a cancer center director, oversight over research funded by several pharmaceutical companies but has not received funding directly herself. The remaining authors declare no conflict of interest. P. Haycock reports grants from Cancer Research UK during the conduct of the study. G. Severi reports grants from Fondation ARC during the conduct of the study. No disclosures were reported by the other authors.

Figures

**Figure 1.**
MR estimates for the association of genetic liability to allergic diseases (asthma, hay fever, or eczema) and individual allergic conditions with the risk of developing colorectal cancer. Results from the IVW approach are depicted.

See this image and copyright information in PMC

References

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229–63. - PubMed
1. Ugai T, Sasamoto N, Lee H-Y, Ando M, Song M, Tamimi RM, et al. . Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat Rev Clin Oncol 2022;19:656–73. - PMC - PubMed
1. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883–99. - PMC - PubMed
1. Hoste E, Cipolat S, Watt FM. Understanding allergy and cancer risk: what are the barriers? Nat Rev Cancer 2015;15:131–2. - PubMed
1. Jacobs EJ, Gapstur SM, Newton CC, Turner MC, Campbell PT. Hay Fever and asthma as markers of atopic immune response and risk of colorectal cancer in three large cohort studies. Cancer Epidemiol Biomarkers Prev 2013;22:661–9. - PubMed

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Association of Genetic Liability to Allergic Diseases with Overall and Early-Onset Colorectal Cancer Risk: A Mendelian Randomization Study

Affiliations

Association of Genetic Liability to Allergic Diseases with Overall and Early-Onset Colorectal Cancer Risk: A Mendelian Randomization Study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical