Impact of atopy on risk of glioma: a Mendelian randomisation study

Linden Disney-Hogg¹, Alex J Cornish¹, Amit Sud¹, Philip J Law¹, Ben Kinnersley¹, Daniel I Jacobs², Quinn T Ostrom³, Karim Labreche¹, Jeanette E Eckel-Passow⁴, Georgina N Armstrong², Elizabeth B Claus^{5

6}, Dora Il'yasova^{7

8

9}, Joellen Schildkraut^{8

9}, Jill S Barnholtz-Sloan³, Sara H Olson¹⁰, Jonine L Bernstein¹⁰, Rose K Lai¹¹, Minouk J Schoemaker¹, Matthias Simon¹², Per Hoffmann^{13

14}, Markus M Nöthen^{14

15}, Karl-Heinz Jöckel¹⁶, Stephen Chanock¹⁷, Preetha Rajaraman¹⁷, Christoffer Johansen^{18

19}, Robert B Jenkins²⁰, Beatrice S Melin²¹, Margaret R Wrensch^{22

23}, Marc Sanson^{24

25}, Melissa L Bondy², Richard S Houlston^{26

27}

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
² Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
³ Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
⁴ Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
⁵ School of Public Health, Yale University, New Haven, CT, USA.
⁶ Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Epidemiology and Biostatistics, School of Public Health, Georgia State University, Atlanta, GA, USA.
⁸ Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
⁹ Cancer Control and Prevention Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
¹⁰ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Departments of Neurology and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹² Department of Neurosurgery, University of Bonn Medical Center, Sigmund-Freud Str. 25, 53105, Bonn, Germany.
¹³ Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
¹⁴ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
¹⁵ Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁶ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA.
¹⁸ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
¹⁹ Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
²⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
²¹ Department of Radiation Sciences, Umeå University, Umeå, Sweden.
²² Department of Neurological Surgery, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
²³ Institute of Human Genetics, University of California, San Francisco, CA, USA.
²⁴ Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, F-75013, Paris, France.
²⁵ AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de neurologie 2-Mazarin, Paris, France.
²⁶ Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK. richard.houlston@icr.ac.uk.
²⁷ Division of Molecular Pathology, The Institute of Cancer Research, London, UK. richard.houlston@icr.ac.uk.

PMID: 29540232
PMCID: PMC5853158
DOI: 10.1186/s12916-018-1027-5

Impact of atopy on risk of glioma: a Mendelian randomisation study

Linden Disney-Hogg et al. BMC Med. 2018.

. 2018 Mar 15;16(1):42.

doi: 10.1186/s12916-018-1027-5.

Authors

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
² Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
³ Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
⁴ Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
⁵ School of Public Health, Yale University, New Haven, CT, USA.
⁶ Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Epidemiology and Biostatistics, School of Public Health, Georgia State University, Atlanta, GA, USA.
⁸ Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
⁹ Cancer Control and Prevention Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
¹⁰ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Departments of Neurology and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹² Department of Neurosurgery, University of Bonn Medical Center, Sigmund-Freud Str. 25, 53105, Bonn, Germany.
¹³ Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
¹⁴ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
¹⁵ Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁶ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA.
¹⁸ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
¹⁹ Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
²⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
²¹ Department of Radiation Sciences, Umeå University, Umeå, Sweden.
²² Department of Neurological Surgery, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
²³ Institute of Human Genetics, University of California, San Francisco, CA, USA.
²⁴ Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, F-75013, Paris, France.
²⁵ AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de neurologie 2-Mazarin, Paris, France.
²⁶ Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK. richard.houlston@icr.ac.uk.
²⁷ Division of Molecular Pathology, The Institute of Cancer Research, London, UK. richard.houlston@icr.ac.uk.

PMID: 29540232
PMCID: PMC5853158
DOI: 10.1186/s12916-018-1027-5

Abstract

Background: An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

Methods: Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis.

Results: Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194).

Conclusions: Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.

Keywords: Allergy; Cancer; Glioma; Mendelian randomisation; Risk.

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Conflict of interest statement

Ethics approval and consent to participate

Two-sample Mendelian randomisation was undertaken using GWAS data. Ethical approval was not sought for this specific project because all data came from the summary statistics of published GWAS, and no individual-level data were used.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
Forest plot of Wald odds ratios (ORs) and 95% confidence intervals generated from single nucleotide polymorphisms (SNPs) associated with atopy-related traits. ORs for individual SNPs are listed according to magnitude of effect in the instrumental variable analysis and are presented with pooled effects using the inverse-variance weighting method. Squares represent the point estimate, and the bars are the 95% confidence intervals. a Asthma and hay fever, b atopic dermatitis, c IgE level, d self-reported allergy

**Fig. 2**
Plot of P value of maximum likelihood estimation associations with glioma against correlation between errors in X_k and Y_k. a Asthma and hay fever, b atopic dermatitis, c IgE level, d self-reported allergy

**Fig. 3**
Scatter plots of genetic associations with glioma against genetic associations with the exposure. a Asthma and hay fever, b atopic dermatitis, c IgE level, d self-reported allergy

See this image and copyright information in PMC

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