Circulating adipokine concentrations and risk of five obesity‐related cancers: A Mendelian randomization study

Abstract

Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity‐related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB‐R] and plasminogen activator inhibitor‐1 [PAI‐1]) with five obesity‐related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary‐level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB‐R and PAI‐1 (P value for inclusion<5 × 10−8). Causal estimates were obtained using two‐sample MR methods. In the inverse‐variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84‐0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB‐R and PAI‐1 were also similarly unrelated to risk of obesity‐related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB‐R and PAI‐1 concentrations on the development of five obesity‐related cancers.

Obesity and Pancreatic Cancer: Insight into Mechanisms

“…In another prospective, nested case-control study, higher leptin levels correlated with an increased risk of pancreatic cancer in men, but not women [92]. Results from a large Mendelian randomization study did not support a causal effect of plasma leptin levels on pancreatic cancer development [93]. In preclinical animal studies, KC mice with DIO developed hyperleptinemia [42,43], suggesting a relationship between leptin and PDAC.…”

Review of Mendelian Randomization Studies on Ovarian Cancer

“…Conversely, a previous large-scale MR study on circulating adiponectin and five obesity-related cancer types does not support an association of tumor progression with concentrations of circulating adiponectin, leptin, sOB-R and PAI-1. The causal relationship between circulating adipokines and development of obesity-related cancers (including OC) is yet to be established ( 42 ).…”

Obesity and Endometrial Cancer

“…Obese patients also have changes in the concentration of insulin-like growth factors and their binding proteins and insulin resistance, all of which may contribute to an increased risk of endometrial cancer in these patients [46]. The triad of obesity, insulin resistance, and adipokine aberrations is linked to cancer [47], since adipokines impair insulin signaling and contribute to insulin resistance [48]. Other mechanisms in pathophysiology are subclinical chronic low-grade inflammation, oxidative stress, and sex hormone biosynthesis [6].…”