Mendelian randomization analyses of 23 known and suspected risk factors and biomarkers for breast cancer overall and by molecular subtypes.
Mendelian randomization analyses of 23 known and suspected risk factors and biomarkers for breast cancer overall and by molecular subtypes.
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DOI：
10.1002/ijc.34026
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发表时间：
2022-08-01
影响因子：
6.4
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中科院分区：
文献类型：
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已确定乳腺癌的许多危险因素。其中一些的潜在因果关系仍不确定，而且很少有研究通过分子亚型全面研究这些关联。我们进行了一项两样本孟德尔随机化 (MR) 研究，利用乳腺癌协会联盟的数据，评估 23 种已知和可疑的风险因素和生物标志物与乳腺癌整体风险和分子亚型之间的潜在因果关系。使用逆方差加权方法来估计每个性状与乳腺癌风险关联的比值比 (OR) 和 95% 置信区间 (CI)。研究发现 15 项特征与乳腺癌风险显着相关，包括初潮年龄、绝经年龄、体重指数、腰臀比、身高、体力活动、吸烟、睡眠时间和早晨偏好的睡眠时间型，以及 6 种血液生物标志物（雌激素、胰岛素样生长因子-1、性激素结合球蛋白 [SHBG]、端粒长度、高密度脂蛋白胆固醇和空腹胰岛素）。值得注意的是，循环SHBG增加与雌激素受体（ER）阳性癌症风险降低相关（OR=0.83，95%CI：0.73-0.94），但ER阴性癌症（OR=1.12，95%CI：0.93-1.36）和三阴性癌症（OR=1.19，95%CI：0.92-1.54）风险升高相关。 （异质性=0.01）。空腹胰岛素与 HER2 阴性癌症风险增加密切相关（OR=1.94，95%CI：1.18–3.20），但与 HER2 富集癌症风险降低相关（OR=0.46，95%CI：0.26–0.81）（异质性=0.006）。使用 MR-Egger 和 MR-PRESSO 进行的敏感性分析结果大体一致。这项研究提供了强有力的证据支持乳腺癌的几种危险因素之间的潜在因果关系，并表明性激素结合球蛋白（SHBG）和空腹胰岛素水平与乳腺癌亚型之间存在潜在的异质关联。
Many risk factors have been identified for breast cancer. The potential causality for some of them remain uncertain, and few studies have comprehensively investigated these associations by molecular subtypes. We performed a two-sample Mendelian randomization (MR) study to evaluate potential causal associations of 23 known and suspected risk factors and biomarkers with breast cancer risk overall and by molecular subtypes using data from the Breast Cancer Association Consortium. The inverse-variance weighted method was used to estimate odds ratios (OR) and 95% confidence interval (CI) for association of each trait with breast cancer risk. Significant associations with breast cancer risk were found for 15 traits, including age at menarche, age at menopause, body mass index, waist-to-hip ratio, height, physical activity, cigarette smoking, sleep duration, and morning-preference chronotype, and six blood biomarkers (estrogens, insulin-like growth factor-1, sex hormone-binding globulin [SHBG], telomere length, HDL-cholesterol, and fasting insulin). Noticeably, an increased circulating SHBG was associated with a reduced risk of estrogen receptor (ER)-positive cancer (OR=0.83, 95%CI: 0.73–0.94), but an elevated risk of ER-negative (OR=1.12, 95%CI: 0.93–1.36) and triple negative cancer (OR=1.19, 95%CI: 0.92–1.54) (Pheterogeneity=0.01). Fasting insulin was most strongly associated with an increased risk of HER2-negative cancer (OR=1.94, 95%CI: 1.18–3.20), but a reduced risk of HER2-enriched cancer (OR=0.46, 95%CI: 0.26–0.81) (Pheterogeneity=0.006). Results from sensitivity analyses using MR-Egger and MR-PRESSO were generally consistent. This study provides strong evidence supporting potential causal associations of several risk factors for breast cancer and suggests potential heterogeneous associations of SHBG and fasting insulin levels with subtypes of breast cancer.
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影响因子：
64.8
作者：
Horikoshi, Momoko;Beaumont, Robin N.;Day, Felix R.;Warrington, Nicole M.;Kooijman, Marjolein N.;Fernandez-Tajes, Juan;Feenstra, Bjarke;van Zuydam, Natalie R.;Gaulton, Kyle J.;Grarup, Niels;Bradfield, Jonathan P.;Strachan, David P.;Li-Gao, Ruifang;Ahluwalia, Tarunveer S.;Kreiner, Eskil;Rueedi, Rico;Lyytikainen, Leo-Pekka;Cousminer, Diana L.;Wu, Ying;Thiering, Elisabeth;Wang, Carol A.;Have, Christian T.;Hottenga, Jouke-Jan;Vilor-Tejedor, Natalia;Joshi, Peter K.;Boh, Eileen Tai Hui;Ntalla, Ioanna;Pitkanen, Niina;Mahajan, Anubha;van Leeuwen, Elisabeth M.;Joro, Raimo;Lagou, Vasiliki;Nodzenski, Michael;Diver, Louise A.;Zondervan, Krina T.;Bustamante, Mariona;Marques-Vidal, Pedro;Mercader, Josep M.;Bennett, Amanda J.;Rahmioglu, Nilufer;Nyholt, Dale R.;Ma, Ronald C. W.;Tam, Claudia H. T.;Tam, Wing Hung;Ganesh, Santhi K.;van Rooij, Frank J. A.;Jones, Samuel E.;Loh, Po-Ru;Ruth, Katherine S.;Tuke, Marcus A.;Tyrrell, Jessica;Wood, Andrew R.;Yaghootkar, Hanieh;Scholtens, Denise M.;Paternoster, Lavinia;Prokopenko, Inga;Kovacs, Peter;Atalay, Mustafa;Willems, Sara M.;Panoutsopoulou, Kalliope;Wang, Xu;Carstensen, Lisbeth;Geller, Frank;Schraut, Katharina E.;Murcia, Mario;van Beijsterveldt, Catharina E. M.;Willemsen, Gonneke;Appel, Emil V. R.;Fonvig, Cilius E.;Trier, Caecilie;Tiesler, Carla M. T.;Standl, Marie;Kutalik, Zoltan;Bonas-Guarch, Silvia;Hougaard, David M.;Sanchez, Friman;Torrents, David;Waage, Johannes;Hollegaard, Mads V.;de Haan, Hugoline G.;Rosendaal, Frits R.;Medina-Gomez, Carolina;Ring, Susan M.;Hemani, Gibran;McMahon, George;Robertson, Neil R.;Groves, Christopher J.;Langenberg, Claudia;Luan, Jian'an;Scott, Robert A.;Zhao, Jing Hua;Mentch, Frank D.;MacKenzie, Scott M.;Reynolds, Rebecca M.;Lowe, William L.;Toenjes, Anke;Stumvoll, Michael;Lindi, Virpi;Lakka, Timo A.;van Duijn, Cornelia M.;Kiess, Wieland;Koerner, Antje;Sorensen, Thorkild I. A.;Niinikoski, Harri;Pahkala, Katja;Raitakari, Olli T.;Zeggini, Eleftheria;Dedoussis, George V.;Teo, Yik-Ying;Saw, Seang-Mei;Melbye, Mads;Campbell, Harry;Wilson, James F.;Vrijheid, Martine;de Geus, Eco J. C. N.;Boomsma, Dorret I.;Kadarmideen, Haja N.;Holm, Jens-Christian;Hansen, Torben;Sebert, Sylvain;Hattersley, Andrew T.;Beilin, Lawrence J.;Newnham, John P.;Pennell, Craig E.;Heinrich, Joachim;Adair, Linda S.;Borja, Judith B.;Mohlke, Karen L.;Eriksson, Johan G.;Widen, Elisabeth;Kahonen, Mika;Viikari, Jorma S.;Lehtimaki, Terho;Vollenweider, Peter;Bonnelykke, Klaus;Bisgaard, Hans;Mook-Kanamori, Dennis O.;Hofman, Albert;Rivadeneira, Fernando;Uitterlinden, Andre G.;Pisinger, Charlotta;Pedersen, Oluf;Power, Christine;Hyppoenen, Elina;Wareham, Nicholas J.;Hakonarson, Hakon;Davies, Eleanor;Walker, Brian R.;Jaddoe, Vincent W. V.;Jaervelin, Marjo-Riitta;Grant, Struan F. A.;Vaag, Allan A.;Lawlor, Debbie A.;Frayling, Timothy M.;Smith, George Davey;Morris, Andrew P.;Ong, Ken K.;Felix, Janine F.;Timpson, Nicholas J.;Perry, John R. B.;Evans, David M.;McCarthy, Mark I.;Freathy, Rachel M.
通讯作者：
Freathy, Rachel M.
影响因子：
51.1
作者：
Key, Timothy J.;Appleby, Paul N.;Reeves, Gillian K.;Roddam, Andrew W.
通讯作者：
Roddam, Andrew W.
影响因子：
7.7
作者：
Jung, Seungyoun;Wang, Molin;Smith-Warner, Stephanie A.
通讯作者：
Smith-Warner, Stephanie A.
影响因子：
7.7
作者：
Beeghly-Fadiel, Alicia;Khankari, Nikhil K.;Zheng, Wei
通讯作者：
Zheng, Wei
影响因子：
9.8
作者：
Li, Chen;Stoma, Svetlana;Codd, Veryan
通讯作者：
Codd, Veryan