Mendelian randomisation study of smoking exposure in relation to breast cancer risk.
Hanla A Park,
Sonja Neumeyer,
Kyriaki Michailidou,
Manjeet K Bolla,
Qin Wang,
Joe Dennis,
Thomas U Ahearn,
Irene L Andrulis,
Hoda Anton-Culver,
Natalia N Antonenkova,
Volker Arndt,
Kristan J Aronson,
Annelie Augustinsson,
Adinda Baten,
Laura E Beane Freeman,
Heiko Becher,
Matthias W Beckmann,
Sabine Behrens,
Javier Benitez,
Marina Bermisheva,
Natalia V Bogdanova,
Stig E Bojesen,
Hiltrud Brauch,
Hermann Brenner,
Sara Y Brucker,
Barbara Burwinkel,
Daniele Campa,
Federico Canzian,
Jose E Castelao,
Stephen J Chanock,
Georgia Chenevix-Trench,
Christine L Clarke,
,
Don M Conroy,
Fergus J Couch,
Angela Cox,
Simon S Cross,
Kamila Czene,
Mary B Daly,
Peter Devilee,
Thilo Dörk,
Isabel Dos-Santos-Silva,
Miriam Dwek,
Diana M Eccles,
A Heather Eliassen,
Christoph Engel,
Mikael Eriksson,
D Gareth Evans,
Peter A Fasching,
Henrik Flyger,
Lin Fritschi,
Montserrat García-Closas,
José A García-Sáenz,
Mia M Gaudet,
Graham G Giles,
Gord Glendon,
Mark S Goldberg,
David E Goldgar,
Anna González-Neira,
Mervi Grip,
Pascal Guénel,
Eric Hahnen,
Christopher A Haiman,
Niclas Håkansson,
Per Hall,
Ute Hamann,
Sileny Han,
Elaine F Harkness,
Steven N Hart,
Wei He,
Bernadette A M Heemskerk-Gerritsen,
John L Hopper,
David J Hunter,
,
,
Agnes Jager,
Anna Jakubowska,
Esther M John,
Audrey Jung,
Rudolf Kaaks,
Pooja Middha Kapoor,
Renske Keeman,
Elza Khusnutdinova,
Cari M Kitahara,
Linetta B Koppert,
Stella Koutros,
Vessela N Kristensen,
Allison W Kurian,
James Lacey,
Diether Lambrechts,
Loic Le Marchand,
Wing-Yee Lo,
Jan Lubiński,
Arto Mannermaa,
Mehdi Manoochehri,
Sara Margolin,
Maria Elena Martinez,
Dimitrios Mavroudis,
Alfons Meindl,
Usha Menon,
Roger L Milne,
Taru A Muranen,
Heli Nevanlinna,
William G Newman,
Børge G Nordestgaard,
Kenneth Offit,
Andrew F Olshan,
Håkan Olsson,
Tjoung-Won Park-Simon,
Paolo Peterlongo,
Julian Peto,
Dijana Plaseska-Karanfilska,
Nadege Presneau,
Paolo Radice,
Gad Rennert,
Hedy S Rennert,
Atocha Romero,
Emmanouil Saloustros,
Elinor J Sawyer,
Marjanka K Schmidt,
Rita K Schmutzler,
Minouk J Schoemaker,
Lukas Schwentner,
Christopher Scott,
Mitul Shah,
Xiao-Ou Shu,
Jacques Simard,
Ann Smeets,
Melissa C Southey,
John J Spinelli,
Victoria Stevens,
Anthony J Swerdlow,
Rulla M Tamimi,
William J Tapper,
Jack A Taylor,
Mary Beth Terry,
Ian Tomlinson,
Melissa A Troester,
Thérèse Truong,
Celine M Vachon,
Elke M van Veen,
Joseph Vijai,
Sophia Wang,
Camilla Wendt,
Robert Winqvist,
Alicja Wolk,
Argyrios Ziogas,
Alison M Dunning,
Paul D P Pharoah,
Douglas F Easton,
Wei Zheng,
Peter Kraft,
Jenny Chang-Claude
Abstract
METHODS
We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.
CONCLUSION
Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
RESULTS
Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.
BACKGROUND
Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.