{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:28:46Z","timestamp":1793647726740,"version":"4.5.1"},"reference-count":18,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"42","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Smoking is an established cause of lung cancer (LC), but the relative causal contributions of whether a person ever smokes and how heavily they smoke across histological subtypes remain uncertain. This study investigated the causal effects of smoking status and smoking intensity on major LC subtypes. Two-sample Mendelian randomization (MR) was performed. Genetic instruments were drawn from the GWAS and Sequencing Consortium of Alcohol and Nicotine Use: 85 variants for smoking status, a binary trait contrasting ever with never smokers, and 23 variants for smoking intensity, a continuous trait measuring cigarettes smoked per day. Outcomes were 5 LC phenotypes from FinnGen: non-small cell LC (1627 cases), adenocarcinoma (571), squamous cell carcinoma (365), small cell LC (179), and mesothelioma (133). Inverse-variance weighted regression with multiplicative random effects was the primary estimator, with weighted median, weighted mode, and MR-Egger as sensitivity analyses. Benjamini\u2013Hochberg correction was applied across all ten tests. Analyses used R 4.2.3 with TwoSampleMR 0.7.9. Smoking intensity was causally associated with all 4 smoking-related subtypes: squamous cell carcinoma (odds ratio [OR]: 5.95 per standard deviation increase, 95% confidence interval [CI]: 3.12\u201311.37), small cell LC (OR: 4.43, 95% CI: 1.60\u201312.32), non-small cell LC (OR: 3.45, 95% CI: 2.30\u20135.18), and adenocarcinoma (OR: 2.66, 95% CI: 1.40\u20135.06). All 4 survived correction for multiple testing and were reproduced by the weighted median and weighted mode estimators. Smoking status showed positive point estimates for all 4 subtypes (OR: 1.40\u20131.61) but reached only nominal significance for non-small cell LC (OR: 1.51, 95% CI: 1.04\u20132.19,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2005=\u2005.030), which did not survive correction and was not reproduced by other estimators. Neither exposure was associated with mesothelioma. Smoking intensity shows robust causal effects on all smoking-related LC subtypes, whereas the evidence for smoking status is directionally consistent but considerably weaker. The null finding for mesothelioma, a cancer principally caused by asbestos, supports the specificity of the instruments. These results indicate that reducing consumption among established smokers warrants emphasis alongside preventing uptake.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/md.0000000000051170","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:01:13Z","timestamp":1792173673000},"page":"e51170","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Contributions of smoking behaviour to lung cancer subtypes"],"prefix":"10.1097","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-1191","authenticated-orcid":false,"given":"Mohammad A.","family":"Jareebi","sequence":"first","affiliation":[{"name":"Department of Family & Community Medicine, College of Medicine, Jazan University, Jazan, Saudi Arabia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0170-1437","authenticated-orcid":false,"given":"Ahmad Y.","family":"Alqassim","sequence":"additional","affiliation":[{"name":"Department of Family & Community Medicine, College of Medicine, Jazan University, Jazan, Saudi Arabia."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20261102","first-page":"394","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"R2-20261102","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1186\/1471-2407-12-385","article-title":"Systematic review with meta-analysis of the epidemiological evidence in the 1900s relating smoking to lung cancer.","volume":"12","author":"Lee","year":"2012","journal-title":"BMC 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randomisation studies: a guide, glossary, and checklist for clinicians.","volume":"362","author":"Davies","year":"2018","journal-title":"BMJ"},{"key":"R7-20261102","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41588-018-0307-5","article-title":"Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.","volume":"51","author":"Liu","year":"2019","journal-title":"Nat Genet"},{"key":"R8-20261102","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/ng.3892","article-title":"Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.","volume":"49","author":"McKay","year":"2017","journal-title":"Nat Genet"},{"key":"R10-20261102","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population.","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"R11-20261102","doi-asserted-by":"crossref","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome.","volume":"7","author":"Hemani","year":"2018","journal-title":"Elife"},{"key":"R12-20261102","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator.","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"key":"R13-20261102","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption.","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int J Epidemiol"},{"key":"R14-20261102","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method.","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur J Epidemiol"},{"key":"R15-20261102","first-page":"1961","article-title":"Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic.","volume":"45","author":"Bowden","year":"2016","journal-title":"Int J Epidemiol"},{"key":"R16-20261102","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1186\/s12885-018-5144-5","article-title":"Risk of lung cancer in relation to various metrics of smoking history: a case-control study in Montreal.","volume":"18","author":"Remen","year":"2018","journal-title":"BMC 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Rep"}],"container-title":["Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1097\/MD.0000000000051170","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:00:54Z","timestamp":1793646054000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1097\/MD.0000000000051170"}},"subtitle":["A two-sample Mendelian randomization study"],"short-title":[],"issued":{"date-parts":[[2026,10,16]]},"references-count":18,"journal-issue":{"issue":"42","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1097\/md.0000000000051170","relation":{},"ISSN":["0025-7974","1536-5964"],"issn-type":[{"value":"0025-7974","type":"print"},{"value":"1536-5964","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,16]]},"assertion":[{"value":"2024-01-04","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}