Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.
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Haycock, Philip C
Wade, Kaitlin H
Relton, Caroline L
Martin, Richard M
Davey Smith, George
Aldrich, Melinda C
Arnold, Susanne M
Bojesen, Stig E
Caporaso, Neil E
Christiani, David C
Christian, W Jay
Doherty, Jennifer A
Duell, Eric J
Field, John K
Davies, Michael P A
Marcus, Michael W
Goodman, Gary E
Kiemeney, Lambertus A
van der Heijden, Erik H F M
Johansson, Mikael B
Landi, Maria Teresa
Le Marchand, Loïc
Park, Sungshim L
Haura, Eric B
Schabath, Matthew B
Teare, M Dawn
Hung, Rayjean J
Amos, Christopher I
MetadataShow full item record
AbstractAssessing 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.
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 = 2.1x10-3), 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.
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.
CitationPLoS ONE 2017, 12 (6):e0177875
SponsorsFunding: RCT, MJ, PCH, KHW, CR, RMM, GDS, and PB are investigators or researchers on a Cancer Research UK (C18281/A19169) Programme Grant (the Integrative Cancer Epidemiology Programme). RMM is supported by the National Institute for Health Research (NIHR) Bristol Nutritional Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. CLR and GDS are supported by funding from the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1, MC_UU_12013/2). PCH is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C52724/A20138). SMA was supported by the Department of Defense under award number: 10153006 (W81XWH-11-1-0781) and by the UK Center for Clinical and Translational Science, (UL1TR000117). JMY is partially supported by the U.S. National Institutes of Health Grants (R01 CA144034 and UM1 CA182876). CARET investigators would like to thank the study participants for their involvement and acknowledge the National Cancer Institute and National Institute of Health for their grant support: 5-UM1-CA-167462, (PI Gary E. Goodman), U01-CA63673 (PIs G. Omenn, G. Goodman), RO1-CA111703 (PI Chu Chen), and 5R01-CA151989-01A1 (PI Jennifer Doherty
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