Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium
Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium
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DOI：
10.1093/ije/dyx242
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发表时间：
2018-04-01
影响因子：
7.7
通讯作者：
Garcia-Closas, Montserrat
中科院分区：
文献类型：
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作者：
Rudolph, Anja;Song, Minsun;Garcia-Closas, Montserrat
背景：乳腺癌的多基因风险评分(PR)可以用来将人群分成不同风险水平的人群。将PR和环境风险因素结合起来将改善风险预测；然而，将PR整合到风险预测模型中需要评估它们与已知环境风险因素的联合关联。方法：分析基于20项研究的数据；分析的数据集范围从3453例到23104例浸润性乳腺癌病例和类似数量的对照，取决于所分析的环境风险因素。我们评估了77个单核苷酸多态(SNP)与生育史、饮酒、绝经激素治疗(MHT)、身高和体重指数(BMI)的联合相关性。我们检验了PR和每个环境因素的乘性联合关联性的零假设，并在Logistic回归模型中进行了全局和基于尾部的拟合优度检验。结果：在ER阳性疾病中，与77位点突变相关的最有力证据是饮酒(P交互作用=0.009)、成人身高(P交互作用=0.025)和目前联合使用甲基羟色胺(P交互作用=0.038)。这些因素的风险关联并不遵循明确的剂量-反应关系。此外，全球和基于尾部的拟合优度测试没有显示偏离乘性风险模型的证据，饮酒显示ER阳性疾病的最有力证据(全球P=0.013，基于尾部的测试为0.18)。结论：77-SNP、PR和环境风险因素对乳腺癌的综合影响通常由乘性模型很好地描述。需要进行更大规模的研究，以确认个体风险因素的乘性模型的可能偏离，并评估ER阴性疾病的特定模型。
Background: Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors.Methods: Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status.Results: The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction = 0.009), adult height (P-interaction = 0.025) and current use of combined MHT (P-interaction = 0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P = 0.013 for global and 0.18 for tail-based tests).Conclusions: The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.