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Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.
Gastroenterology ( IF 25.7 ) Pub Date : 2019-12-27 , DOI: 10.1053/j.gastro.2019.12.020 Neil Murphy 1 , Robert Carreras-Torres 2 , Mingyang Song 3 , Andrew T Chan 4 , Richard M Martin 5 , Nikos Papadimitriou 1 , Niki Dimou 1 , Konstantinos K Tsilidis 6 , Barbara Banbury 7 , Kathryn E Bradbury 8 , Jelena Besevic 9 , Sabina Rinaldi 1 , Elio Riboli 9 , Amanda J Cross 9 , Ruth C Travis 10 , Claudia Agnoli 11 , Demetrius Albanes 12 , Sonja I Berndt 12 , Stéphane Bézieau 13 , D Timothy Bishop 14 , Hermann Brenner 15 , Daniel D Buchanan 16 , N Charlotte Onland-Moret 17 , Andrea Burnett-Hartman 18 , Peter T Campbell 19 , Graham Casey 20 , Sergi Castellví-Bel 21 , Jenny Chang-Claude 22 , María-Dolores Chirlaque 23 , Albert de la Chapelle 24 , Dallas English 25 , Jane C Figueiredo 26 , Steven J Gallinger 27 , Graham G Giles 28 , Stephen B Gruber 29 , Andrea Gsur 30 , Jochen Hampe 31 , Heather Hampel 32 , Tabitha A Harrison 7 , Michael Hoffmeister 33 , Li Hsu 34 , Wen-Yi Huang 12 , Jeroen R Huyghe 7 , Mark A Jenkins 35 , Temitope O Keku 36 , Tilman Kühn 22 , Sun-Seog Kweon 37 , Loic Le Marchand 38 , Christopher I Li 7 , Li Li 39 , Annika Lindblom 40 , Vicente Martín 41 , Roger L Milne 28 , Victor Moreno 42 , Polly A Newcomb 43 , Kenneth Offit 44 , Shuji Ogino 45 , Jennifer Ose 46 , Vittorio Perduca 47 , Amanda I Phipps 48 , Elizabeth A Platz 49 , John D Potter 50 , Conghui Qu 7 , Gad Rennert 51 , Lori C Sakoda 52 , Clemens Schafmayer 53 , Robert E Schoen 54 , Martha L Slattery 55 , Catherine M Tangen 56 , Cornelia M Ulrich 46 , Franzel J B van Duijnhoven 57 , Bethany Van Guelpen 58 , Kala Visvanathan 49 , Pavel Vodicka 59 , Ludmila Vodickova 59 , Veronika Vymetalkova 59 , Hansong Wang 38 , Emily White 48 , Alicja Wolk 60 , Michael O Woods 61 , Anna H Wu 62 , Wei Zheng 63 , Ulrike Peters 48 , Marc J Gunter 1
Gastroenterology ( IF 25.7 ) Pub Date : 2019-12-27 , DOI: 10.1053/j.gastro.2019.12.020 Neil Murphy 1 , Robert Carreras-Torres 2 , Mingyang Song 3 , Andrew T Chan 4 , Richard M Martin 5 , Nikos Papadimitriou 1 , Niki Dimou 1 , Konstantinos K Tsilidis 6 , Barbara Banbury 7 , Kathryn E Bradbury 8 , Jelena Besevic 9 , Sabina Rinaldi 1 , Elio Riboli 9 , Amanda J Cross 9 , Ruth C Travis 10 , Claudia Agnoli 11 , Demetrius Albanes 12 , Sonja I Berndt 12 , Stéphane Bézieau 13 , D Timothy Bishop 14 , Hermann Brenner 15 , Daniel D Buchanan 16 , N Charlotte Onland-Moret 17 , Andrea Burnett-Hartman 18 , Peter T Campbell 19 , Graham Casey 20 , Sergi Castellví-Bel 21 , Jenny Chang-Claude 22 , María-Dolores Chirlaque 23 , Albert de la Chapelle 24 , Dallas English 25 , Jane C Figueiredo 26 , Steven J Gallinger 27 , Graham G Giles 28 , Stephen B Gruber 29 , Andrea Gsur 30 , Jochen Hampe 31 , Heather Hampel 32 , Tabitha A Harrison 7 , Michael Hoffmeister 33 , Li Hsu 34 , Wen-Yi Huang 12 , Jeroen R Huyghe 7 , Mark A Jenkins 35 , Temitope O Keku 36 , Tilman Kühn 22 , Sun-Seog Kweon 37 , Loic Le Marchand 38 , Christopher I Li 7 , Li Li 39 , Annika Lindblom 40 , Vicente Martín 41 , Roger L Milne 28 , Victor Moreno 42 , Polly A Newcomb 43 , Kenneth Offit 44 , Shuji Ogino 45 , Jennifer Ose 46 , Vittorio Perduca 47 , Amanda I Phipps 48 , Elizabeth A Platz 49 , John D Potter 50 , Conghui Qu 7 , Gad Rennert 51 , Lori C Sakoda 52 , Clemens Schafmayer 53 , Robert E Schoen 54 , Martha L Slattery 55 , Catherine M Tangen 56 , Cornelia M Ulrich 46 , Franzel J B van Duijnhoven 57 , Bethany Van Guelpen 58 , Kala Visvanathan 49 , Pavel Vodicka 59 , Ludmila Vodickova 59 , Veronika Vymetalkova 59 , Hansong Wang 38 , Emily White 48 , Alicja Wolk 60 , Michael O Woods 61 , Anna H Wu 62 , Wei Zheng 63 , Ulrike Peters 48 , Marc J Gunter 1
Affiliation
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BACKGROUND & AIMS
Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.
METHODS
Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.
CONCLUSIONS
In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
中文翻译：
根据血清学和孟德尔随机分析，胰岛素样生长因子 1 和胰岛素样生长因子结合蛋白 3 的循环水平与结直肠癌的风险相关。
背景与目的 人体研究检查了胰岛素样生长因子 1 (IGF1) 和胰岛素样生长因子结合蛋白 3 (IGFBP3) 的循环水平与结直肠癌风险之间的关联，但结果不一致。我们进行了补充血清学和孟德尔随机化 (MR) 分析，以确定 IGF1 或 IGFBP3 循环水平的变化是否与结直肠癌的发展相关。方法 对 2006 年至 2010 年从英国生物银行收集的 397,380 名参与者的血液样本中测量 IGF1 的血清水平。通过与国家癌症和死亡登记处的联系来识别癌症事件病例和死亡证明中首先记录的癌症病例。完整的随访截至 2016 年 3 月 31 日。对于 MR 分析，我们确定了与 IGF1 和 IGFBP3 循环水平相关的遗传变异。使用全基因组关联研究联盟数据（52,865 例结直肠癌病例和 46,287 例无[对照]的个体），通过 2 样本 MR 方法检查了这些遗传变异与结直肠癌的关联。 结果：中位随访期 7.1 年后多年来，记录了 2665 例结直肠癌病例。在多变量调整模型中，IGF1 的循环水平与结直肠癌风险相关（IGF1 每 1 个标准差增量的风险比为 1.11；95% 置信区间 [CI] 1.05-1.17）。性别、随访时间和肿瘤亚位点也发现了类似的关联。在 MR 分析中，根据遗传因素预测，IGF1 水平增加 1 个标准差与结直肠癌风险较高相关（比值比 1.08；95% CI 1.03-1.12；P = 3.3 × 10-4） 。 根据遗传因素预测的 IGFBP3 水平与结直肠癌风险相关（每 1 个标准差增量的优势比为 1.12；95% CI 1.06-1.18；P = 4.2 × 10-5）。结直肠癌风险仅与 IGFBP3 基因区域 (rs11977526) 的 1 个变异相关，该变异也与人体测量特征和 IGF2 循环水平相关。结论 通过对英国生物银行近 400,000 名参与者的血液样本进行分析，我们发现 IGF1 的循环水平与结直肠癌之间存在关联。使用 52,865 名结直肠癌病例和 46,287 名对照者的遗传数据发现，由遗传因素决定的较高水平的 IGF1 与结直肠癌相关。需要进一步的研究来确定该信号通路如何促进结直肠癌的发生。
更新日期：2020-04-21
中文翻译：
根据血清学和孟德尔随机分析，胰岛素样生长因子 1 和胰岛素样生长因子结合蛋白 3 的循环水平与结直肠癌的风险相关。
背景与目的 人体研究检查了胰岛素样生长因子 1 (IGF1) 和胰岛素样生长因子结合蛋白 3 (IGFBP3) 的循环水平与结直肠癌风险之间的关联，但结果不一致。我们进行了补充血清学和孟德尔随机化 (MR) 分析，以确定 IGF1 或 IGFBP3 循环水平的变化是否与结直肠癌的发展相关。方法 对 2006 年至 2010 年从英国生物银行收集的 397,380 名参与者的血液样本中测量 IGF1 的血清水平。通过与国家癌症和死亡登记处的联系来识别癌症事件病例和死亡证明中首先记录的癌症病例。完整的随访截至 2016 年 3 月 31 日。对于 MR 分析，我们确定了与 IGF1 和 IGFBP3 循环水平相关的遗传变异。使用全基因组关联研究联盟数据（52,865 例结直肠癌病例和 46,287 例无[对照]的个体），通过 2 样本 MR 方法检查了这些遗传变异与结直肠癌的关联。 结果：中位随访期 7.1 年后多年来，记录了 2665 例结直肠癌病例。在多变量调整模型中，IGF1 的循环水平与结直肠癌风险相关（IGF1 每 1 个标准差增量的风险比为 1.11；95% 置信区间 [CI] 1.05-1.17）。性别、随访时间和肿瘤亚位点也发现了类似的关联。在 MR 分析中，根据遗传因素预测，IGF1 水平增加 1 个标准差与结直肠癌风险较高相关（比值比 1.08；95% CI 1.03-1.12；P = 3.3 × 10-4） 。 根据遗传因素预测的 IGFBP3 水平与结直肠癌风险相关（每 1 个标准差增量的优势比为 1.12；95% CI 1.06-1.18；P = 4.2 × 10-5）。结直肠癌风险仅与 IGFBP3 基因区域 (rs11977526) 的 1 个变异相关，该变异也与人体测量特征和 IGF2 循环水平相关。结论 通过对英国生物银行近 400,000 名参与者的血液样本进行分析，我们发现 IGF1 的循环水平与结直肠癌之间存在关联。使用 52,865 名结直肠癌病例和 46,287 名对照者的遗传数据发现，由遗传因素决定的较高水平的 IGF1 与结直肠癌相关。需要进一步的研究来确定该信号通路如何促进结直肠癌的发生。
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