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[Preprint]. 2023 May 5:2023.05.04.23289196.

doi: 10.1101/2023.05.04.23289196.

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis

James Yarmolinsky^{1

2}, Jamie W Robinson^{1

2}, Daniela Mariosa³, Ville Karhunen^{4

5}, Jian Huang^{6

7}, Niki Dimou⁸, Neil Murphy⁸, Kimberley Burrows^{1

2}, Emmanouil Bouras⁹, Karl Smith-Byrne¹⁰, Sarah J Lewis^{1

2}, Tessel E Galesloot¹¹, Lambertus A Kiemeney¹¹, Sita Vermeulen¹², Paul Martin¹³, Demetrius Albanes¹⁴, Lifang Hou¹⁵, Polly A Newcomb^{16

17}, Emily White^{16

18}, Alicja Wolk¹⁹, Anna H Wu²⁰, Loïc Le Marchand²¹, Amanda I Phipps^{16

18}, Daniel D Buchanan^{22

23

24}; International Lung Cancer Consortium, PRACTICAL consortium; Sizheng Steven Zhao²⁵, Dipender Gill⁶, Stephen J Chanock²⁶, Mark P Purdue²⁶, George Davey Smith^{1

2}, Paul Brennan³, Karl-Heinz Herzig^{27

28}, Marjo-Riitta Jarvelin^{4

29

30

31}, Abbas Dehghan^{6

28

32}, Mattias Johansson³, Marc J Gunter⁸, Kostas K Tsilidis^{6

9}, Richard M Martin^{1

2

33}

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
⁴ Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁵ Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland.
⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London.
⁷ Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
⁸ Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
⁹ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
¹⁰ The Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
¹¹ Radboud University Medical Center, Nijmegen, The Netherlands.
¹² Department for Health Evidence, Radboudumc, Nijmegen, The Netherlands.
¹³ School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, UK.
¹⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁵ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁷ School of Public Health, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
¹⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁰ University of Southern California, Preventative Medicine, Los Angeles, California, USA.
²¹ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA 22.
²² Colorectal Oncogenomic Group, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.
²³ Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia.
²⁴ Genetic Medicine and Family Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
²⁵ Centre for Epidemiology Versus Arthritis, Faculty of Biological Medicine and Health, University of Manchester, Manchester, UK.
²⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
²⁷ Institute of Biomedicine, Medical Research Center and Oulu University Hospital, University of Oulu, Finland.
²⁸ Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland.
²⁹ MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³⁰ Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
³¹ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom.
³² Dementia Research Institute, Imperial College London, London, UK.
³³ University Hospitals Bristol and Weston NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK.

PMID: 37205426
PMCID: PMC10187459
DOI: 10.1101/2023.05.04.23289196

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis

James Yarmolinsky et al. medRxiv. 2023.

[Preprint]. 2023 May 5:2023.05.04.23289196.

doi: 10.1101/2023.05.04.23289196.

Authors

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
⁴ Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁵ Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland.
⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London.
⁷ Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
⁸ Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
⁹ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
¹⁰ The Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
¹¹ Radboud University Medical Center, Nijmegen, The Netherlands.
¹² Department for Health Evidence, Radboudumc, Nijmegen, The Netherlands.
¹³ School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, UK.
¹⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁵ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁷ School of Public Health, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
¹⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁰ University of Southern California, Preventative Medicine, Los Angeles, California, USA.
²¹ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA 22.
²² Colorectal Oncogenomic Group, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.
²³ Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia.
²⁴ Genetic Medicine and Family Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
²⁵ Centre for Epidemiology Versus Arthritis, Faculty of Biological Medicine and Health, University of Manchester, Manchester, UK.
²⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
²⁷ Institute of Biomedicine, Medical Research Center and Oulu University Hospital, University of Oulu, Finland.
²⁸ Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland.
²⁹ MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³⁰ Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
³¹ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom.
³² Dementia Research Institute, Imperial College London, London, UK.
³³ University Hospitals Bristol and Weston NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK.

PMID: 37205426
PMCID: PMC10187459
DOI: 10.1101/2023.05.04.23289196

Update in

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.
Yarmolinsky J, Robinson JW, Mariosa D, Karhunen V, Huang J, Dimou N, Murphy N, Burrows K, Bouras E, Smith-Byrne K, Lewis SJ, Galesloot TE, Kiemeney LA, Vermeulen S, Martin P, Albanes D, Hou L, Newcomb PA, White E, Wolk A, Wu AH, Le Marchand L, Phipps AI, Buchanan DD; International Lung Cancer Consortium; PRACTICAL Consortium; Zhao SS, Gill D, Chanock SJ, Purdue MP, Davey Smith G, Brennan P, Herzig KH, Järvelin MR, Amos CI, Hung RJ, Dehghan A, Johansson M, Gunter MJ, Tsilidis KK, Martin RM. Yarmolinsky J, et al. EBioMedicine. 2024 Feb;100:104991. doi: 10.1016/j.ebiom.2024.104991. Epub 2024 Feb 1. EBioMedicine. 2024. PMID: 38301482 Free PMC article.

Abstract

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 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 x 10^-8) cis-acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r² < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH₄) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes.

Results: 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%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q-value=0.072, PPH₄=76.1%), 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%). 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.

Conclusion: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 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.

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References

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This is a preprint.

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis

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Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis

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