학술논문
Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysisResearch in context
Document Type
article
Author
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; Christopher I. Amos; Sanjay Shete; Heike Bickeböller; Angela Risch; Richard Houlston; Stephen Lam; Adonina Tardon; Chu Chen; Stig E. Bojesen; H-Erich Wichmann; David Christiani; Gadi Rennert; Susanne Arnold; John K. Field; Loic Le Marchand; Olle Melander; Hans Brunnström; Geoffrey Liu; Angeline Andrew; 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; Catherine M. Tangen; Jyotsna Batra; Judith A. Clements; Henrik Grönberg; Nora Pashayan; Johanna Schleutker; Stephanie J. Weinstein; 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
Source
EBioMedicine, Vol 100, Iss , Pp 104991- (2024)
Subject
Language
English
ISSN
2352-3964
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).