1. Genetics and Genomics

Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization

  1. Mark Gormley  Is a corresponding author
  2. Tom Dudding
  3. Steven J Thomas
  4. Jessica Tyrrell
  5. Andrew R Ness
  6. Miranda Pring
  7. Danny Legge
  8. George Davey Smith
  9. Rebecca C Richmond
  10. Emma E Vincent
  11. Caroline Bull
  1. University of Bristol, United Kingdom
  2. University of Exeter, United Kingdom
https://doi.org/10.7554/eLife.82674
Share this article
Cite this article
  1. Mark Gormley
  2. Tom Dudding
  3. Steven J Thomas
  4. Jessica Tyrrell
  5. Andrew R Ness
  6. Miranda Pring
  7. Danny Legge
  8. George Davey Smith
  9. Rebecca C Richmond
  10. Emma E Vincent
  11. Caroline Bull
(2023)
Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization
eLife 12:e82674.
https://doi.org/10.7554/eLife.82674
  2. Download BibTeX
  3. Download .RIS

Abstract

A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted (IVW) method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data was taken from the largest available GWAS of 6,034 oral and oropharyngeal cases, with 6,585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (OR IVW = 0.89, 95%CI 0.72-1.09, p = 0.26 per 1 SD in BMI (4.81 kg/m2)) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including type 2 diabetes and hypertension.

Data availability

Summary-level analysis was conducted using publicly available GWAS data as cited. Full summary statistics for the GAME-ON outcome data GWAS can be accessed via dbGAP (OncoArray: Oral and Pharynx Cancer; study accession number: phs001202.v1.p1, August 2017) at: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001202.v1.p1) (Lesseur et al., 2016). This data is also available via the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk/).All exposure data used in this study is publicly available from the relevant studies as described below. Data for BMI, WC and WHR GWAS was downloaded from the Genetic Investigation of ANthropometric Traits (GIANT) consortiumhttps://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files (Pulit et al., 2019; Shungin et al., 2015) and UK Biobank (http://www.ukbiobank.ac.uk). T2D data was downloaded from the DIAMANTE (DIAbetes Meta-ANalysis of Trans-Ethnic association studies) consortium from: https://kp4cd.org/node/169 (Vujkovic et al., 2020). Data for FG, FI and HbA1c, were obtained from GWAS published by the MAGIC (Meta-Analyses of Glucose and Insulin-Related Traits) Consortium, available for download from: https://magicinvestigators.org/downloads/ (Lagou et al., 2021),. Finally, data for SBP and DBP were extracted from a GWAS meta-analysis of participants in UK Biobank (and UK Biobank (http://www.ukbiobank.ac.uk) and the International Consortium of Blood Pressure Genome Wide Association Studies (ICBP), available via dbGAP (International Consortium for Blood Pressure (ICBP), study accession number: phs000585.v2.p1, October 2016) at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000585.v2.p1 (Evangelou et al., 2018).Instrument-risk factor analysis outcome summary-level data were derived from the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN) and UK Biobank and UK Biobank (http://www.ukbiobank.ac.uk) for alcoholic drinks per week https://conservancy.umn.edu/handle/11299/201564 (Liu et al., 2019) and the comprehensive smoking index (Wootton et al., 2019). Data for risk tolerance and educational attainment were taken from Social Science Genetic Association Consortium (SSGAC) data available from http://www.thessgac.org/data (Karlsson Linner et al., 2019; J. Lee et al., 2018). MR analyses were conducted using the 'TwoSampleMR' package in R (version 3.5.3). A copy of the code and all data files used in this study are available at GitHub (https://github.com/MGormley12/metabolic_trait_hnc_mr.git).

The following previously published data sets were used
    1. Vujkovic M
    2. et al
    (2020) DIAMANTE (European) T2D GWAS
    DIAMANTE (DIAbetes Meta-ANalysis of Trans-Ethnic association studies).
    https://kp4cd.org/node/169

Article and author information

Author details

  1. Mark Gormley

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    For correspondence
    mark.gormley@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5733-6304

  2. Tom Dudding

    Bristol Dental Hospital and School, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Steven J Thomas

    Bristol Dental Hospital and School, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Jessica Tyrrell

    Medical School, University of Exeter, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Andrew R Ness

    University Hospitals Bristol and Weston NHS Foundation Trust, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Miranda Pring

    Bristol Dental Hospital and School, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. Danny Legge

    Translational Health Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3897-5861

  8. George Davey Smith

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1407-8314

  9. Rebecca C Richmond

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  10. Emma E Vincent

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8917-7384

  11. Caroline Bull

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2176-5120

Funding

Wellcome Trust (220530/Z/20/Z)

  • Mark Gormley

Diabetes UK (SBF004\1079)

  • Jessica Tyrrell

National Institute for Health and Care Research (RP-PG-0707-10034)

  • Andrew R Ness

Cancer Research UK (C18281/A20919)

  • Andrew R Ness

National Institute of Dental and Craniofacial Research (R01 DE025712 and 1X01HG007780-0)

  • Andrew R Ness

Diabetes UK (17/0005587)

  • Emma E Vincent

World Cancer Research Fund (IIG_2019_2009)

  • Emma E Vincent

Medical Research Council (MC_UU_00011/1,MC_UU_00011/5,MC_UU_00011/6,MC_UU_00011/7)

  • George Davey Smith

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Publicly available summary level data only used in this study. Application entitled "Investigating aetiology, associations and causality in diseases of the head and neck" (Project ID: 40644) covers use of all UK Biobank data in this study and dbGaP application made for accessing OncoArray: Oral and Pharynx Cancer; study accession number: phs001202.v1.p1 data entitled "Investigating risk factors in head and neck cancer using Mendelianrandomization" (Project ID 24266).

Copyright

© 2023, Gormley et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,209
    views
  • 169
    downloads
  • 23
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Mark Gormley
  2. Tom Dudding
  3. Steven J Thomas
  4. Jessica Tyrrell
  5. Andrew R Ness
  6. Miranda Pring
  7. Danny Legge
  8. George Davey Smith
  9. Rebecca C Richmond
  10. Emma E Vincent
  11. Caroline Bull
(2023)
Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization
eLife 12:e82674.
https://doi.org/10.7554/eLife.82674

Share this article

https://doi.org/10.7554/eLife.82674

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Genetics and Genomics

    DNA replication in primary hepatocytes without the six-subunit ORC

    Róża K Przanowska, Yuechuan Chen ... Anindya Dutta
    Research Article

    The six-subunit ORC is essential for the initiation of DNA replication in eukaryotes. Cancer cell lines in culture can survive and replicate DNA replication after genetic inactivation of individual ORC subunits, ORC1, ORC2, or ORC5. In primary cells, ORC1 was dispensable in the mouse liver for endo-reduplication, but this could be explained by the ORC1 homolog, CDC6, substituting for ORC1 to restore functional ORC. Here, we have created mice with a conditional deletion of ORC2, which does not have a homolog. Although mouse embryo fibroblasts require ORC2 for proliferation, mouse hepatocytes synthesize DNA in cell culture and endo-reduplicate in vivo without ORC2. Mouse livers endo-reduplicate after simultaneous deletion of ORC1 and ORC2 both during normal development and after partial hepatectomy. Since endo-reduplication initiates DNA synthesis like normal S phase replication these results unequivocally indicate that primary cells, like cancer cell lines, can load MCM2-7 and initiate replication without ORC.

    1. Genetics and Genomics
    2. Neuroscience

    Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli

    Martina Rudgalvyte, Zehan Hu ... Dominique A Glauser
    Research Article

    Thermal nociception in Caenorhabditis elegans is regulated by the Ca²+/calmodulin-dependent protein kinase CMK-1, but its downstream effectors have remained unclear. Here, we combined in vitro kinase assays with mass-spectrometry-based phosphoproteomics to identify hundreds of CMK-1 substrates, including the calcineurin A subunit TAX-6, phosphorylated within its conserved regulatory domain. Genetic and pharmacological analyses reveal multiple antagonistic interactions between CMK-1 and calcineurin signaling in modulating both naive thermal responsiveness and adaptation to repeated noxious stimuli. Cell-specific manipulations indicate that CMK-1 acts in AFD and ASER thermo-sensory neurons, while TAX-6 functions in FLP thermo-sensory neurons and downstream interneurons. Since CMK-1 and TAX-6 act in distinct cell types, the phosphorylation observed in vitro might not directly underlie the behavioral phenotype. Instead, the opposing effects seem to arise from their distributed roles within the sensory circuit. Overall, our study provides (1) a resource of candidate CMK-1 targets for further dissecting CaM kinase signaling and (2) evidence of a previously unrecognized, circuit-level antagonism between CMK-1 and calcineurin pathways. These findings highlight a complex interplay of signaling modules that modulate thermal nociception and adaptation, offering new insights into potentially conserved mechanisms that shape nociceptive plasticity and pain (de)sensitization in more complex nervous systems.

    1. Genetics and Genomics

    IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming

    Mengjia Li, Hengchao Zhang ... Lixiang Chen
    Research Article

    Isocitrate dehydrogenase 1 (IDH1) is the key enzyme that can modulate cellular metabolism, epigenetic modification, and redox homeostasis. Gain-of-function mutations and decreased expression of IDH1 have been demonstrated to be associated with pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the function and mechanism of IDH1 in human erythropoiesis still remains unclear. Here, utilizing the human erythropoiesis system, we present an evidence of IDH1-mediated chromatin state reprogramming besides its well-characterized metabolism effects. We found that knockdown IDH1 induced chromatin reorganization and subsequently led to abnormalities biological events in erythroid precursors, which could not be rescued by addition of reactive oxygen species (ROS) scavengers or supplementation of α-ketoglutarate (α-KG).We further revealed that knockdown IDH1 induces genome-wide changes in distribution and intensity of multiple histone marks, among which H3K79me3 was identified as a critical factor in chromatin state reprogramming. Integrated analysis of ChIP-seq, ATAC-seq, and RNA-seq recognized that SIRT1 was the key gene affected by IDH1 deficiency. Thus, our current work provided novel insights for further clarifying fundamental biological function of IDH1 which has substantial implications for an in-depth understanding of pathogenesis of diseases with IDH1 dysfunction and accordingly development of therapeutic strategies.