Line Rode1, Stig E Bojesen1, Maren Weischer1, Børge G Nordestgaard2. 1. Department of Clinical Biochemistry and The Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 2. Department of Clinical Biochemistry and The Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark boerge.nordestgaard@regionh.dk.
Abstract
BACKGROUND: High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality. METHODS: We studied 55,568 individuals including 32,823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses. RESULTS: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend<0.001). Second, the observational multivariable adjusted hazard ratio for all-cause mortality was 1.12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with -13 base pairs (-18, -8) per doubling in tobacco consumption. In Mendelian randomization analysis, the estimate was +3 base pairs (-10, +15) per minor CHRNA3 allele. Finally, individuals with the shortest vs longest telomeres had a multivariable adjusted hazard ratio of 1.30 (1.13, 1.50) for all-cause mortality; however, in mediation analysis short telomeres explained only +0.4% (-3.5%, +4.3%) of the association between high tobacco consumption and increased all-cause mortality. CONCLUSIONS: High tobacco consumption is causally associated with increased all-cause mortality. High cumulative tobacco consumption is associated with short telomeres observationally, but there is no clear genetic association.
BACKGROUND: High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality. METHODS: We studied 55,568 individuals including 32,823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses. RESULTS: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend<0.001). Second, the observational multivariable adjusted hazard ratio for all-cause mortality was 1.12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with -13 base pairs (-18, -8) per doubling in tobacco consumption. In Mendelian randomization analysis, the estimate was +3 base pairs (-10, +15) per minor CHRNA3 allele. Finally, individuals with the shortest vs longest telomeres had a multivariable adjusted hazard ratio of 1.30 (1.13, 1.50) for all-cause mortality; however, in mediation analysis short telomeres explained only +0.4% (-3.5%, +4.3%) of the association between high tobacco consumption and increased all-cause mortality. CONCLUSIONS: High tobacco consumption is causally associated with increased all-cause mortality. High cumulative tobacco consumption is associated with short telomeres observationally, but there is no clear genetic association.
Authors: Julia Raschenberger; Barbara Kollerits; James Ritchie; Beverley Lane; Philip A Kalra; Eberhard Ritz; Florian Kronenberg Journal: Sci Rep Date: 2015-07-07 Impact factor: 4.379
Authors: Glenda Lassi; Amy E Taylor; Nicholas J Timpson; Paul J Kenny; Robert J Mather; Tim Eisen; Marcus R Munafò Journal: Trends Neurosci Date: 2016-11-18 Impact factor: 13.837
Authors: Allan Linneberg; Rikke K Jacobsen; Tea Skaaby; Amy E Taylor; Meg E Fluharty; Jørgen L Jeppesen; Johan H Bjorngaard; Bjørn O Åsvold; Maiken E Gabrielsen; Archie Campbell; Riccardo E Marioni; Meena Kumari; Pedro Marques-Vidal; Marika Kaakinen; Alana Cavadino; Iris Postmus; Tarunveer S Ahluwalia; S Goya Wannamethee; Jari Lahti; Katri Räikkönen; Aarno Palotie; Andrew Wong; Christine Dalgård; Ian Ford; Yoav Ben-Shlomo; Lene Christiansen; Kirsten O Kyvik; Diana Kuh; Johan G Eriksson; Peter H Whincup; Hamdi Mbarek; Eco J C de Geus; Jacqueline M Vink; Dorret I Boomsma; George Davey Smith; Debbie A Lawlor; Aliaksei Kisialiou; Alex McConnachie; Sandosh Padmanabhan; J Wouter Jukema; Chris Power; Elina Hyppönen; Martin Preisig; Gerard Waeber; Peter Vollenweider; Tellervo Korhonen; Tiina Laatikainen; Veikko Salomaa; Jaakko Kaprio; Mika Kivimaki; Blair H Smith; Caroline Hayward; Thorkild I A Sørensen; Betina H Thuesen; Naveed Sattar; Richard W Morris; Pål R Romundstad; Marcus R Munafò; Marjo-Riitta Jarvelin; Lise Lotte N Husemoen Journal: Circ Cardiovasc Genet Date: 2015-11-04
Authors: Daniel I Swerdlow; Karoline B Kuchenbaecker; Sonia Shah; Reecha Sofat; Michael V Holmes; Jon White; Jennifer S Mindell; Mika Kivimaki; Eric J Brunner; John C Whittaker; Juan P Casas; Aroon D Hingorani Journal: Int J Epidemiol Date: 2016-06-24 Impact factor: 7.196