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

• DOI: 10.1371/journal.pone.0177875
• Publication Date: 2017-06-08T13:39:50Z
• Authors: Robert Carreras-T...; 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. Kiem...; Erik H. F. M. van...; 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
• Keywords: Lung Neoplasms; smoking habits; Physiology; Epidemiology; Biochemistry; Lung and Intrathoracic Tumors; Body Mass Index; /dk/atira/pure/core/keywords/icep; Small Cell Lung Cancer; Habits; Endocrinology; Hàbit de fumar; Risk Factors; Medicine and Health Sciences; Smoking Habits; 2.1 Biological and endogenous factors; Insulin; Aetiology; Lung; Cancer; 2. Zero hunger; Likelihood Functions; 0303 health sciences; Lung Cancer; Q; R; Single Nucleotide; Fasting; Tobbacco habit; Lipids; 3. Good health; Cholesterol; Phenotype; Oncology; Physiological Parameters; Physical Sciences; Medicine; Anatomy; Lung cancer; Statistics (Mathematics); Research Article; Histology; General Science & Technology; Science; Oncology and Carcinogenesis; 610; Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; Polymorphism, Single Nucleotide; BMI; 03 medical and health sciences; Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences; Clinical Research; Health Sciences; Tobacco; Confidence Intervals; Genetics; Journal Article; Humans; Obesity; Polymorphism; Nutrition; /dk/atira/pure/core/keywords/icep; name=ICEP; Diabetic Endocrinology; Behavior; Cancer och onkologi; Biomedical and Clinical Sciences; Tobacco Smoke and Health; name=ICEP; Prevention; Body Weight; Cancers and Neoplasms; Biology and Life Sciences; Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences; Mendelian Randomization Analysis; Hormones; lung cancer; Cancer and Oncology; Càncer de pulmó; Insulin Resistance; Mathematics

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.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.