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

Abstract

BackgroundAssessing 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 findingsWe 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.ConclusionsOur 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.

A Prospective Study of Obesity, Metabolic Health, and Cancer Mortality

“…Though still the subject of much debate, there is compelling evidence that obesity status itself may be a less informative risk or prognostic factor for many diseases, including cancer. In fact, our findings as well as others (29,30) have indicated that metabolic health status may be a more important cancer prognostic factor that should be evaluated in addition to obesity. We observed a consistently higher risk of cancer mortality among metabolically unhealthy participants with normal weight, with associations that were significantly higher when focused on obesity-related cancers.…”

BMI and Mortality in UK Biobank: Revised Estimates Using Mendelian Randomization

“…Mendelian randomization (MR) is a well-documented application of instrumental variable (IV) methodology using genetic variants (most commonly, single-nucleotide polymorphisms [SNPs]) as IVs to provide relatively unbiased causal estimates of the effect of an exposure (i.e., BMI) on an outcome (i.e., mortality) (14,15). MR has provided evidence to support a causal effect of higher BMI increasing the risk of cardiovascular diseases (CVDs), diabetes, cardiometabolic traits, and various cancers (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). However, no study has explicitly used MR to explore the causal role of BMI in all-cause and cause-specific mortality.…”

Independent and joint associations of blood lipids and lipoproteins with lung cancer risk in Chinese males: A prospective cohort study

“…Furthermore, as established risk factors for chronic disease that are routinely measured in the clinic, total cholesterol (TC), triglycerides (TG), low‐density lipoprotein cholesterol (LDL‐C), and high‐density lipoprotein cholesterol (HDL‐C) have been associated with cancer risk in a substantial number of studies . Since the 1980s, several epidemiological studies have investigated the associations of TC, TG, and HDL‐C with lung cancer risk but have shown markedly contrasting results due to differences in the classification of smoking status, lack of prospective cohort study designs, relatively modest sample sizes and other potential biases . In addition, the relationship between blood lipids, such as LDL‐C and non‐HDL‐C, and lung cancer risk has been less investigated and remains unclear.…”

“…6 Since the 1980s, several epidemiological studies have investigated the associations of TC, TG, and HDL-C with lung cancer risk but have shown markedly contrasting results due to differences in the classification of smoking status, lack of prospective cohort study designs, relatively modest sample sizes and other potential biases. [7][8][9][10][11][12][13][14][15][16][17][18][19] In addition, the relationship between blood lipids, such as LDL-C and non-HDL-C, and lung cancer risk has been less investigated and remains unclear. Furthermore, to our knowledge, no study has focused on the joint impact of blood lipids and lipoproteins on lung cancer risk.…”