EBioMedicine (Feb 2024)
Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysisResearch in context
- James Yarmolinsky,
- Jamie W. Robinson,
- Daniela Mariosa,
- Ville Karhunen,
- Jian Huang,
- Niki Dimou,
- Neil Murphy,
- Kimberley Burrows,
- Emmanouil Bouras,
- Karl Smith-Byrne,
- Sarah J. Lewis,
- Tessel E. Galesloot,
- Lambertus A. Kiemeney,
- Sita Vermeulen,
- Paul Martin,
- Demetrius Albanes,
- Lifang Hou,
- Polly A. Newcomb,
- Emily White,
- Alicja Wolk,
- Anna H. Wu,
- Loïc Le Marchand,
- Amanda I. Phipps,
- Daniel D. Buchanan,
- Sizheng Steven Zhao,
- Dipender Gill,
- Stephen J. Chanock,
- Mark P. Purdue,
- George Davey Smith,
- Paul Brennan,
- Karl-Heinz Herzig,
- Marjo-Riitta Järvelin,
- Chris I. Amos,
- Rayjean J. Hung,
- Abbas Dehghan,
- Mattias Johansson,
- Marc J. Gunter,
- Kostas K. Tsilidis,
- Richard M. Martin,
- Maria Teresa Landi,
- Victoria Stevens,
- Ying Wang,
- Demetrios Albanes,
- Neil Caporaso,
- Paul Brennan,
- Christopher I. Amos,
- Sanjay Shete,
- Rayjean J. Hung,
- Heike Bickeböller,
- Angela Risch,
- Richard Houlston,
- Stephen Lam,
- Adonina Tardon,
- Chu Chen,
- Stig E. Bojesen,
- Mattias Johansson,
- H-Erich Wichmann,
- David Christiani,
- Gadi Rennert,
- Susanne Arnold,
- John K. Field,
- Loic Le Marchand,
- Olle Melander,
- Hans Brunnström,
- Geoffrey Liu,
- Angeline Andrew,
- Lambertus A. Kiemeney,
- Hongbing Shen,
- Shan Zienolddiny,
- Kjell Grankvist,
- Mikael Johansson,
- M. Dawn Teare,
- Yun-Chul Hong,
- Jian-Min Yuan,
- Philip Lazarus,
- Matthew B. Schabath,
- Melinda C. Aldrich,
- Rosalind A. Eeles,
- Christopher A. Haiman,
- Zsofia Kote-Jarai,
- Fredrick R. Schumacher,
- Sara Benlloch,
- Ali Amin Al Olama,
- Kenneth R. Muir,
- Sonja I. Berndt,
- David V. Conti,
- Fredrik Wiklund,
- Stephen Chanock,
- Ying Wang,
- Catherine M. Tangen,
- Jyotsna Batra,
- Judith A. Clements,
- Henrik Grönberg,
- Nora Pashayan,
- Johanna Schleutker,
- Demetrius Albanes,
- Stephanie J. Weinstein,
- Alicja Wolk,
- Catharine M.L. West,
- Lorelei A. Mucci,
- Géraldine Cancel-Tassin,
- Stella Koutros,
- Karina Dalsgaard Sørensen,
- Eli Marie Grindedal,
- David E. Neal,
- Freddie C. Hamdy,
- Jenny L. Donovan,
- Ruth C. Travis,
- Robert J. Hamilton,
- Sue Ann Ingles,
- Barry S. Rosenstein,
- Yong-Jie Lu,
- Graham G. Giles,
- Robert J. MacInnis,
- Adam S. Kibel,
- Ana Vega,
- Manolis Kogevinas,
- Kathryn L. Penney,
- Jong Y. Park,
- Janet L. Stanfrod,
- Cezary Cybulski,
- Børge G. Nordestgaard,
- Sune F. Nielsen,
- Hermann Brenner,
- Christiane Maier,
- Christopher J. Logothetis,
- Esther M. John,
- Manuel R. Teixeira,
- Susan L. Neuhausen,
- Kim De Ruyck,
- Azad Razack,
- Lisa F. Newcomb,
- Davor Lessel,
- Radka Kaneva,
- Nawaid Usmani,
- Frank Claessens,
- Paul A. Townsend,
- Jose Esteban Castelao,
- Monique J. Roobol,
- Florence Menegaux,
- Kay-Tee Khaw,
- Lisa Cannon-Albright,
- Hardev Pandha,
- Stephen N. Thibodeau,
- David J. Hunter,
- Peter Kraft,
- William J. Blot,
- Elio Riboli
Affiliations
- James Yarmolinsky
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Corresponding author. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
- Jamie W. Robinson
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Daniela Mariosa
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Ville Karhunen
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland; Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
- Jian Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
- Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Kimberley Burrows
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Karl Smith-Byrne
- The Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Sarah J. Lewis
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Tessel E. Galesloot
- Radboud University Medical Center, Nijmegen, The Netherlands
- Lambertus A. Kiemeney
- Radboud University Medical Center, Nijmegen, The Netherlands
- Sita Vermeulen
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
- Paul Martin
- School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, UK
- Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Lifang Hou
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; School of Public Health, University of Washington, Seattle, WA, USA
- Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
- Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Anna H. Wu
- University of Southern California, Preventative Medicine, Los Angeles, CA, USA
- Loïc Le Marchand
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
- Amanda I. Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
- Daniel D. Buchanan
- Colorectal Oncogenomic Group, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia; Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia; Genetic Medicine and Family Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
- Sizheng Steven Zhao
- Centre for Epidemiology Versus Arthritis, Faculty of Biological Medicine and Health, University of Manchester, Manchester, UK
- Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK
- Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
- Mark P. Purdue
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
- George Davey Smith
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Paul Brennan
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Karl-Heinz Herzig
- Institute of Biomedicine, Medical Research Center and Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
- Marjo-Riitta Järvelin
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France; Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK
- Chris I. Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
- Rayjean J. Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
- Abbas Dehghan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Dementia Research Institute, Imperial College London, London, UK
- Mattias Johansson
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Marc J. Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Kostas K. Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Richard M. Martin
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; University Hospitals Bristol and Weston NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK
- Maria Teresa Landi
- Victoria Stevens
- Ying Wang
- Demetrios Albanes
- Neil Caporaso
- Paul Brennan
- Christopher I. Amos
- Sanjay Shete
- Rayjean J. Hung
- Heike Bickeböller
- Angela Risch
- Richard Houlston
- Stephen Lam
- Adonina Tardon
- Chu Chen
- Stig E. Bojesen
- Mattias Johansson
- H-Erich Wichmann
- David Christiani
- Gadi Rennert
- Susanne Arnold
- John K. Field
- Loic Le Marchand
- Olle Melander
- Hans Brunnström
- Geoffrey Liu
- Angeline Andrew
- Lambertus A. Kiemeney
- Hongbing Shen
- Shan Zienolddiny
- Kjell Grankvist
- Mikael Johansson
- M. Dawn Teare
- Yun-Chul Hong
- Jian-Min Yuan
- Philip Lazarus
- Matthew B. Schabath
- Melinda C. Aldrich
- Rosalind A. Eeles
- Christopher A. Haiman
- Zsofia Kote-Jarai
- Fredrick R. Schumacher
- Sara Benlloch
- Ali Amin Al Olama
- Kenneth R. Muir
- Sonja I. Berndt
- David V. Conti
- Fredrik Wiklund
- Stephen Chanock
- Ying Wang
- Catherine M. Tangen
- Jyotsna Batra
- Judith A. Clements
- Henrik Grönberg
- Nora Pashayan
- Johanna Schleutker
- Demetrius Albanes
- Stephanie J. Weinstein
- Alicja Wolk
- Catharine M.L. West
- Lorelei A. Mucci
- Géraldine Cancel-Tassin
- Stella Koutros
- Karina Dalsgaard Sørensen
- Eli Marie Grindedal
- David E. Neal
- Freddie C. Hamdy
- Jenny L. Donovan
- Ruth C. Travis
- Robert J. Hamilton
- Sue Ann Ingles
- Barry S. Rosenstein
- Yong-Jie Lu
- Graham G. Giles
- Robert J. MacInnis
- Adam S. Kibel
- Ana Vega
- Manolis Kogevinas
- Kathryn L. Penney
- Jong Y. Park
- Janet L. Stanfrod
- Cezary Cybulski
- Børge G. Nordestgaard
- Sune F. Nielsen
- Hermann Brenner
- Christiane Maier
- Christopher J. Logothetis
- Esther M. John
- Manuel R. Teixeira
- Susan L. Neuhausen
- Kim De Ruyck
- Azad Razack
- Lisa F. Newcomb
- Davor Lessel
- Radka Kaneva
- Nawaid Usmani
- Frank Claessens
- Paul A. Townsend
- Jose Esteban Castelao
- Monique J. Roobol
- Florence Menegaux
- Kay-Tee Khaw
- Lisa Cannon-Albright
- Hardev Pandha
- Stephen N. Thibodeau
- David J. Hunter
- Peter Kraft
- William J. Blot
- Elio Riboli
- Journal volume & issue
-
Vol. 100
p. 104991
Abstract
Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
