The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study.
The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study.
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DOI：
10.1093/jnci/djx012
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发表时间：
2017-09-01
期刊：
影响因子：
--
通讯作者：
Brennan P
中科院分区：
文献类型：
--
作者：
Carreras-Torres R;Johansson M;Gaborieau V;Haycock PC;Wade KH;Relton CL;Martin RM;Davey Smith G;Brennan P
胰腺癌的风险因素包括一系列代谢疾病，如肥胖、高血压、血脂异常、胰岛素抵抗和2型糖尿病。考虑到这些风险因素是相关的，将因果关系与混杂效应分开是具有挑战性的。孟德尔随机化（MR）或使用遗传工具变量可能有助于识别胰腺癌的代谢驱动因素。我们确定了肥胖、体型、血脂异常、胰岛素抵抗和2型糖尿病的遗传因素，以评估它们在胰腺癌病因学中的因果作用。使用来自胰腺癌队列联盟（PanScan）和胰腺癌病例对照联盟（PanC4）的全基因组数据，在一系列7110例胰腺癌患者和7264例对照受试者中使用基于可能性的MR方法分析这些工具与风险的关系。使用加权中位数方法和MR-Egger敏感性分析评估潜在的未知多效性效应。结果表明，体重指数（BMI）增加与胰腺癌风险存在强有力的因果关系（BMI每增加一个标准差[4.6 kg/m2]，比值比[OR]= 1.34，95%置信区间[CI]= 1.09至1.65）。还有证据表明，遗传性空腹胰岛素水平升高与胰腺癌风险升高存在因果关系（OR = 1.66，95% CI = 1.05 - 2.63，每SD [44.4 pmol/L]）。值得注意的是，未观察到与2型糖尿病或血脂异常存在因果关系的证据。敏感性分析并未表明多效性是偏倚的重要来源。我们的研究结果提示BMI和空腹胰岛素在胰腺癌病因中的因果作用。
Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer. We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk using a likelihood-based MR approach within a series of 7110 pancreatic cancer patients and 7264 control subjects using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Potential unknown pleiotropic effects were assessed using a weighted median approach and MR-Egger sensitivity analyses. Results indicated a robust causal association of increasing body mass index (BMI) with pancreatic cancer risk (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.09 to 1.65, for each standard deviation increase in BMI [4.6 kg/m2]). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR = 1.66, 95% CI = 1.05 to 2.63, per SD [44.4 pmol/L]). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Sensitivity analyses did not indicate that pleiotropy was an important source of bias. Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.
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影响因子：
7.7
作者：
Burgess S
通讯作者：
Burgess S
影响因子：
15.9
作者：
Kahn, BB;Flier, JS
通讯作者：
Flier, JS
影响因子：
16.2
作者：
Esposito K;Chiodini P;Colao A;Lenzi A;Giugliano D
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Giugliano D
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
30.8
作者：
Childs EJ;Mocci E;Campa D;Bracci PM;Gallinger S;Goggins M;Li D;Neale RE;Olson SH;Scelo G;Amundadottir LT;Bamlet WR;Bijlsma MF;Blackford A;Borges M;Brennan P;Brenner H;Bueno-de-Mesquita HB;Canzian F;Capurso G;Cavestro GM;Chaffee KG;Chanock SJ;Cleary SP;Cotterchio M;Foretova L;Fuchs C;Funel N;Gazouli M;Hassan M;Herman JM;Holcatova I;Holly EA;Hoover RN;Hung RJ;Janout V;Key TJ;Kupcinskas J;Kurtz RC;Landi S;Lu L;Malecka-Panas E;Mambrini A;Mohelnikova-Duchonova B;Neoptolemos JP;Oberg AL;Orlow I;Pasquali C;Pezzilli R;Rizzato C;Saldia A;Scarpa A;Stolzenberg-Solomon RZ;Strobel O;Tavano F;Vashist YK;Vodicka P;Wolpin BM;Yu H;Petersen GM;Risch HA;Klein AP
通讯作者：
Klein AP