Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
Section of Genetics, International Agency for Research on Cancer, Lyon, France.
Int J Cancer. 2021 Apr 1;148(7):1625-1636. doi: 10.1002/ijc.33338. Epub 2020 Oct 26.
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 ). 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.
肥胖被认为是一种慢性炎症状态，其特征是持续分泌脂肪因子和细胞因子。实验和流行病学证据表明，循环脂肪因子可能与肥胖相关癌症的发展有关，但这些关联是因果关系还是混杂因素尚不清楚。我们使用孟德尔随机化 (MR) 方法研究了特定脂肪因子（脂联素、瘦素、可溶性瘦素受体 [sOB-R] 和纤溶酶原激活物抑制剂-1 [PAI-1]）与五种肥胖相关癌症（结直肠癌、胰腺癌、肾细胞癌 [RCC]、卵巢癌和子宫内膜癌）之间的潜在因果关联。我们使用大型遗传联合体的汇总水平数据，纳入了 114530 例癌症病例和 245284 例对照。我们使用 18 个与脂联素相关的遗传变异、2 个与瘦素相关的遗传变异和 4 个与 sOB-R 和 PAI-1 相关的遗传变异来构建遗传工具（纳入的 P 值均<5×10）。使用两样本 MR 方法获得因果估计值。在逆方差加权模型中，我们发现脂联素与结直肠癌风险呈负相关（脂联素浓度每增加 1μg/mL，比值比：0.90[95%置信区间=0.84-0.97]；P=0.01）；但检测到水平性混杂，当考虑到这一点时，该关联并不存在。脂联素与胰腺癌、RCC、卵巢癌和子宫内膜癌的风险无关联。瘦素、sOB-R 和 PAI-1 与肥胖相关癌症的风险也没有关联。尽管样本量很大，但我们的 MR 分析不支持循环脂联素、瘦素、sOB-R 和 PAI-1 浓度对五种肥胖相关癌症发展的因果影响。
