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Causal effects of body mass index on airflow obstruction and forced mid-expiratory flow: a Mendelian randomization study taking interactions and age-specific instruments Into consideration toward a life course perspective

Causal effects of body mass index on airflow obstruction and forced mid-expiratory flow: a Mendelian randomization study taking interactions and age-specific instruments Into consideration toward a life course perspective
Causal effects of body mass index on airflow obstruction and forced mid-expiratory flow: a Mendelian randomization study taking interactions and age-specific instruments Into consideration toward a life course perspective
Obesity has complex links to respiratory health. Mendelian randomization (MR) enables assessment of causality of body mass index (BMI) effects on airflow obstruction and mid-expiratory flow. In the adult SAPALDIA cohort, recruiting 9,651 population-representative samples aged 18–60 years at baseline (female 51%), BMI and the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) as well as forced mid-expiratory flow (FEF25–75%) were measured three times over 20 follow-up years. The causal effects of BMI in childhood and adulthood on FEV1/FVC and FEF25–75% were assessed in predictive (BMI averaged over 1st and 2nd, lung function (LF) averaged over 2nd and 3rd follow-up; N = 2,850) and long-term cross-sectional models (BMI and LF averaged over all follow-ups; N = 2,728) by Mendelian Randomization analyses with the use of weighted BMI allele score as an instrument variable and two-stage least squares (2SLS) method. Three different BMI allele scores were applied to specifically capture the part of BMI in adulthood that likely reflects tracking of genetically determined BMI in childhood. The main causal effects were derived from models containing BMI (instrumented by BMI genetic score), age, sex, height, and packyears smoked as covariates. BMI interactions were instrumented by the product of the instrument (BMI genetic score) and the relevant concomitant variable. Causal effects of BMI on FEV1/FVC and FEF25–75% were observed in both the predictive and long-term cross-sectional models. The causal BMI- LF effects were negative and attenuated with increasing age, and stronger if instrumented by gene scores associated with childhood BMI. This non-standard MR approach interrogating causal effects of multiplicative interaction suggests that the genetically rooted part of BMI patterns in childhood may be of particular relevance for the level of small airway function and airflow obstruction later in life. The methodological relevance of the results is first to point to the importance of a life course perspective in studies on the etiological role of BMI in respiratory health, and second to point out novel methodological aspects to be considered in future MR studies on the causal effects of obesity related phenotypes.
COPD, Mendelian randomization, body mass index, genetic score, longitudinal cohort, lung function
2296-2565
584955
Probst-Hensch, Nicole
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Jeong, Ayoung
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Stolz, Daiana
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Pons, Marco
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Soccal, Paola M
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Bettschart, Robert
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Jarvis, Deborah
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Holloway, John W
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Kronenberg, Florian
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Imboden, Medea
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Schindler, Christian
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Lovison, Gianfranco F
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Probst-Hensch, Nicole
33ee3cca-a1d4-4157-87c3-20ebfd84406f
Jeong, Ayoung
d742adca-f0fd-4da7-89ba-a01b5e879664
Stolz, Daiana
859570d3-63c3-48e5-a47e-ff8a185d807b
Pons, Marco
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Soccal, Paola M
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Bettschart, Robert
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Jarvis, Deborah
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Holloway, John W
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Kronenberg, Florian
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Imboden, Medea
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Schindler, Christian
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Lovison, Gianfranco F
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Probst-Hensch, Nicole, Jeong, Ayoung, Stolz, Daiana, Pons, Marco, Soccal, Paola M, Bettschart, Robert, Jarvis, Deborah, Holloway, John W, Kronenberg, Florian, Imboden, Medea, Schindler, Christian and Lovison, Gianfranco F (2021) Causal effects of body mass index on airflow obstruction and forced mid-expiratory flow: a Mendelian randomization study taking interactions and age-specific instruments Into consideration toward a life course perspective. Frontiers in Public Health, 9, 584955, [584955]. (doi:10.3389/fpubh.2021.584955).

Record type: Article

Abstract

Obesity has complex links to respiratory health. Mendelian randomization (MR) enables assessment of causality of body mass index (BMI) effects on airflow obstruction and mid-expiratory flow. In the adult SAPALDIA cohort, recruiting 9,651 population-representative samples aged 18–60 years at baseline (female 51%), BMI and the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) as well as forced mid-expiratory flow (FEF25–75%) were measured three times over 20 follow-up years. The causal effects of BMI in childhood and adulthood on FEV1/FVC and FEF25–75% were assessed in predictive (BMI averaged over 1st and 2nd, lung function (LF) averaged over 2nd and 3rd follow-up; N = 2,850) and long-term cross-sectional models (BMI and LF averaged over all follow-ups; N = 2,728) by Mendelian Randomization analyses with the use of weighted BMI allele score as an instrument variable and two-stage least squares (2SLS) method. Three different BMI allele scores were applied to specifically capture the part of BMI in adulthood that likely reflects tracking of genetically determined BMI in childhood. The main causal effects were derived from models containing BMI (instrumented by BMI genetic score), age, sex, height, and packyears smoked as covariates. BMI interactions were instrumented by the product of the instrument (BMI genetic score) and the relevant concomitant variable. Causal effects of BMI on FEV1/FVC and FEF25–75% were observed in both the predictive and long-term cross-sectional models. The causal BMI- LF effects were negative and attenuated with increasing age, and stronger if instrumented by gene scores associated with childhood BMI. This non-standard MR approach interrogating causal effects of multiplicative interaction suggests that the genetically rooted part of BMI patterns in childhood may be of particular relevance for the level of small airway function and airflow obstruction later in life. The methodological relevance of the results is first to point to the importance of a life course perspective in studies on the etiological role of BMI in respiratory health, and second to point out novel methodological aspects to be considered in future MR studies on the causal effects of obesity related phenotypes.

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Accepted/In Press date: 1 April 2021
Published date: 11 May 2021
Additional Information: Funding Information: This work was supported by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement no. 633212 (ALEC Study). SAPALDIA has been supported since its onset by the Swiss National Science Foundation (SNF Grant Nos. 33CS30-177506/1, 33CS30-148470/2, 33CS30-148470/1, 33CSCO-134276/1, 33CSCO-108796, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, PMPDP3_129021/1, and PMPDP3_141671/1); the Swiss Federal Office for the Environment; the Federal Office of Public Health; the Federal Office of Roads and Transport; the canton’s government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich; the Swiss Lung League; the canton’s Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticino, Valais, Graubünden and Zurich; Stiftung ehemals Bündner Heilstätten; SUVA; Freiwillige Akademische Gesellschaft; UBS Wealth Foundation; European Commission [grant agreement . . . (GABRIEL)]; Wellcome Trust (grant agreement . . .). Funding Information: Funding. This work was supported by the European Union's Horizon 2020 Research and Innovation programme under grant agreement no. 633212 (ALEC Study). SAPALDIA has been supported since its onset by the Swiss National Science Foundation (SNF Grant Nos. 33CS30-177506/1, 33CS30-148470/2, 33CS30-148470/1, 33CSCO-134276/1, 33CSCO-108796, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, PMPDP3_129021/1, and PMPDP3_141671/1); the Swiss Federal Office for the Environment; the Federal Office of Public Health; the Federal Office of Roads and Transport; the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Z?rich; the Swiss Lung League; the canton's Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticino, Valais, Graub?nden and Zurich; Stiftung ehemals B?ndner Heilst?tten; SUVA; Freiwillige Akademische Gesellschaft; UBS Wealth Foundation; European Commission [grant agreement.. (GABRIEL)]; Wellcome Trust (grant agreement..). Publisher Copyright: © Copyright © 2021 Probst-Hensch, Jeong, Stolz, Pons, Soccal, Bettschart, Jarvis, Holloway, Kronenberg, Imboden, Schindler and Lovison.
Keywords: COPD, Mendelian randomization, body mass index, genetic score, longitudinal cohort, lung function

Identifiers

Local EPrints ID: 449161
URI: http://eprints.soton.ac.uk/id/eprint/449161
ISSN: 2296-2565
PURE UUID: d878dc78-cfee-459e-9cb1-22c8c915a29d
ORCID for John W Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 18 May 2021 16:33
Last modified: 17 Mar 2024 02:45

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Contributors

Author: Nicole Probst-Hensch
Author: Ayoung Jeong
Author: Daiana Stolz
Author: Marco Pons
Author: Paola M Soccal
Author: Robert Bettschart
Author: Deborah Jarvis
Author: John W Holloway ORCID iD
Author: Florian Kronenberg
Author: Medea Imboden
Author: Christian Schindler
Author: Gianfranco F Lovison

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