Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

Robert Carreras-Torres; Mattias Johansson; Philip C Haycock; Kaitlin H Wade; Caroline L Relton; Richard M Martin; George Davey Smith; Demetrius Albanes; Melinda C Aldrich; Angeline Andrew; Susanne M Arnold; Heike Bickeböller; Stig E Bojesen; Hans Brunnström; Jonas Manjer; Irene Brüske; Neil E Caporaso; Chu Chen; David C Christiani; W Jay Christian; Jennifer A Doherty; Eric J Duell; John K Field; Michael P A Davies; Michael W Marcus; Gary E Goodman; Kjell Grankvist; Aage Haugen; Yun-Chul Hong; Lambertus A Kiemeney; Erik H F M van der Heijden; Peter Kraft; Mikael B Johansson; Stephen Lam; Maria Teresa Landi; Philip Lazarus; Loïc Le Marchand; Geoffrey Liu; Olle Melander; Sungshim L Park; Gad Rennert; Angela Risch; Eric B Haura; Ghislaine Scelo; David Zaridze; Anush Mukeriya; Milan Savić; Jolanta Lissowska; Beata Swiatkowska; Vladimir Janout; Ivana Holcatova; Dana Mates; Matthew B Schabath; Hongbing Shen; Adonina Tardon; M Dawn Teare; Penella Woll; Ming-Sound Tsao; Xifeng Wu; Jian-Min Yuan; Rayjean J Hung; Christopher I Amos; James McKay; Paul Brennan

doi:10.1371/journal.pone.0177875

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

Robert Carreras-Torres, Mattias Johansson, Philip C Haycock, Kaitlin H Wade, Caroline L Relton, Richard M Martin, George Davey Smith, Demetrius Albanes, Melinda C Aldrich, Angeline Andrew, Susanne M Arnold, Heike Bickeböller, Stig E Bojesen, Hans Brunnström, Jonas Manjer, Irene Brüske, Neil E Caporaso, Chu Chen, David C Christiani, W Jay ChristianJennifer A Doherty, Eric J Duell, John K Field, Michael P A Davies, Michael W Marcus, Gary E Goodman, Kjell Grankvist, Aage Haugen, Yun-Chul Hong, Lambertus A Kiemeney, Erik H F M van der Heijden, Peter Kraft, Mikael B Johansson, Stephen Lam, Maria Teresa Landi, Philip Lazarus, Loïc Le Marchand, Geoffrey Liu, Olle Melander, Sungshim L Park, Gad Rennert, Angela Risch, Eric B Haura, Ghislaine Scelo, David Zaridze, Anush Mukeriya, Milan Savić, Jolanta Lissowska, Beata Swiatkowska, Vladimir Janout, Ivana Holcatova, Dana Mates, Matthew B Schabath, Hongbing Shen, Adonina Tardon, M Dawn Teare, Penella Woll, Ming-Sound Tsao, Xifeng Wu, Jian-Min Yuan, Rayjean J Hung, Christopher I Amos, James McKay, Paul Brennan

Institut for Klinisk Medicin

42 Citationer (Scopus)

52 Downloads (Pure)

Abstract

Background Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m²]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (P_{heterogeneity} = 4.3x10^-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1×10^-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

Originalsprog	Engelsk
Artikelnummer	e0177875
Tidsskrift	PloS one
Vol/bind	12
Udgave nummer	6
Antal sider	16
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0177875
Status	Udgivet - jun. 2017

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Carreras-Torres, R., Johansson, M., Haycock, P. C., Wade, K. H., Relton, C. L., Martin, R. M., Davey Smith, G., Albanes, D., Aldrich, M. C., Andrew, A., Arnold, S. M., Bickeböller, H., Bojesen, S. E., Brunnström, H., Manjer, J., Brüske, I., Caporaso, N. E., Chen, C., Christiani, D. C., ... Brennan, P. (2017). Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study. PloS one, 12(6), Artikel e0177875. https://doi.org/10.1371/journal.pone.0177875

Carreras-Torres, R, Johansson, M, Haycock, PC, Wade, KH, Relton, CL, Martin, RM, Davey Smith, G, Albanes, D, Aldrich, MC, Andrew, A, Arnold, SM, Bickeböller, H, Bojesen, SE, Brunnström, H, Manjer, J, Brüske, I, Caporaso, NE, Chen, C, Christiani, DC, Christian, WJ, Doherty, JA, Duell, EJ, Field, JK, Davies, MPA, Marcus, MW, Goodman, GE, Grankvist, K, Haugen, A, Hong, Y-C, Kiemeney, LA, van der Heijden, EHFM, Kraft, P, Johansson, MB, Lam, S, Landi, MT, Lazarus, P, Le Marchand, L, Liu, G, Melander, O, Park, SL, Rennert, G, Risch, A, Haura, EB, Scelo, G, Zaridze, D, Mukeriya, A, Savić, M, Lissowska, J, Swiatkowska, B, Janout, V, Holcatova, I, Mates, D, Schabath, MB, Shen, H, Tardon, A, Teare, MD, Woll, P, Tsao, M-S, Wu, X, Yuan, J-M, Hung, RJ, Amos, CI, McKay, J & Brennan, P 2017, 'Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study', PloS one, bind 12, nr. 6, e0177875. https://doi.org/10.1371/journal.pone.0177875

@article{bcf801856b964e7fac7c154f808c774b,

title = "Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study",

abstract = "Background Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1×10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.",

keywords = "Body Mass Index, Fasting, Humans, Insulin, Insulin Resistance, Likelihood Functions, Lipids, Lung Neoplasms, Mendelian Randomization Analysis, Obesity, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Journal Article",

author = "Robert Carreras-Torres and Mattias Johansson and Haycock, {Philip C} and Wade, {Kaitlin H} and Relton, {Caroline L} and Martin, {Richard M} and {Davey Smith}, George and Demetrius Albanes and Aldrich, {Melinda C} and Angeline Andrew and Arnold, {Susanne M} and Heike Bickeb{\"o}ller and Bojesen, {Stig E} and Hans Brunnstr{\"o}m and Jonas Manjer and Irene Br{\"u}ske and Caporaso, {Neil E} and Chu Chen and Christiani, {David C} and Christian, {W Jay} and Doherty, {Jennifer A} and Duell, {Eric J} and Field, {John K} and Davies, {Michael P A} and Marcus, {Michael W} and Goodman, {Gary E} and Kjell Grankvist and Aage Haugen and Yun-Chul Hong and Kiemeney, {Lambertus A} and {van der Heijden}, {Erik H F M} and Peter Kraft and Johansson, {Mikael B} and Stephen Lam and Landi, {Maria Teresa} and Philip Lazarus and {Le Marchand}, Lo{\"i}c and Geoffrey Liu and Olle Melander and Park, {Sungshim L} and Gad Rennert and Angela Risch and Haura, {Eric B} and Ghislaine Scelo and David Zaridze and Anush Mukeriya and Milan Savi{\'c} and Jolanta Lissowska and Beata Swiatkowska and Vladimir Janout and Ivana Holcatova and Dana Mates and Schabath, {Matthew B} and Hongbing Shen and Adonina Tardon and Teare, {M Dawn} and Penella Woll and Ming-Sound Tsao and Xifeng Wu and Jian-Min Yuan and Hung, {Rayjean J} and Amos, {Christopher I} and James McKay and Paul Brennan",

year = "2017",

month = jun,

doi = "10.1371/journal.pone.0177875",

language = "English",

volume = "12",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "6",

}

TY - JOUR

T1 - Obesity, metabolic factors and risk of different histological types of lung cancer

T2 - A Mendelian randomization study

AU - Carreras-Torres, Robert

AU - Johansson, Mattias

AU - Haycock, Philip C

AU - Wade, Kaitlin H

AU - Relton, Caroline L

AU - Martin, Richard M

AU - Davey Smith, George

AU - Albanes, Demetrius

AU - Aldrich, Melinda C

AU - Andrew, Angeline

AU - Arnold, Susanne M

AU - Bickeböller, Heike

AU - Bojesen, Stig E

AU - Brunnström, Hans

AU - Manjer, Jonas

AU - Brüske, Irene

AU - Caporaso, Neil E

AU - Chen, Chu

AU - Christiani, David C

AU - Christian, W Jay

AU - Doherty, Jennifer A

AU - Duell, Eric J

AU - Field, John K

AU - Davies, Michael P A

AU - Marcus, Michael W

AU - Goodman, Gary E

AU - Grankvist, Kjell

AU - Haugen, Aage

AU - Hong, Yun-Chul

AU - Kiemeney, Lambertus A

AU - van der Heijden, Erik H F M

AU - Kraft, Peter

AU - Johansson, Mikael B

AU - Lam, Stephen

AU - Landi, Maria Teresa

AU - Lazarus, Philip

AU - Le Marchand, Loïc

AU - Liu, Geoffrey

AU - Melander, Olle

AU - Park, Sungshim L

AU - Rennert, Gad

AU - Risch, Angela

AU - Haura, Eric B

AU - Scelo, Ghislaine

AU - Zaridze, David

AU - Mukeriya, Anush

AU - Savić, Milan

AU - Lissowska, Jolanta

AU - Swiatkowska, Beata

AU - Janout, Vladimir

AU - Holcatova, Ivana

AU - Mates, Dana

AU - Schabath, Matthew B

AU - Shen, Hongbing

AU - Tardon, Adonina

AU - Teare, M Dawn

AU - Woll, Penella

AU - Tsao, Ming-Sound

AU - Wu, Xifeng

AU - Yuan, Jian-Min

AU - Hung, Rayjean J

AU - Amos, Christopher I

AU - McKay, James

AU - Brennan, Paul

PY - 2017/6

Y1 - 2017/6

N2 - Background Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1×10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

AB - Background Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1×10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

KW - Body Mass Index

KW - Fasting

KW - Humans

KW - Insulin

KW - Insulin Resistance

KW - Likelihood Functions

KW - Lipids

KW - Lung Neoplasms

KW - Mendelian Randomization Analysis

KW - Obesity

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Journal Article

U2 - 10.1371/journal.pone.0177875

DO - 10.1371/journal.pone.0177875

M3 - Journal article

C2 - 28594918

SN - 1932-6203

VL - 12

JO - PloS one

JF - PloS one

IS - 6

M1 - e0177875

ER -

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

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