Genetic Susceptibility And The Environment In Cancer Risk

维生素D具有抗癌和免疫相关的特性，可以预防一些疾病，包括乳腺癌。维生素D影响基因转录，并可能影响DNA甲基化。 我们使用非西班牙裔白色女性的病例队列样本（1070例，1277例亚队列）研究了血清维生素D、DNA甲基化和乳腺癌之间的关系。对于我们的初步分析，我们使用稳健的线性回归来检查队列（“子队列”）的随机样本中血清25-羟基维生素D（25（OH）D）和甲基化之间的关联。我们专注于7个维生素D相关基因中或附近的198个CpG。对于这198个候选CpG位点，我们还研究了甲基化和25（OH）D之间的乘法相互作用如何与乳腺癌风险相关。这是使用考克斯比例风险模型和全病例队列样本完成的。我们还进行了一项探索性的表观基因组关联研究（EWAS），研究子队列中25（OH）D与DNA甲基化之间的关联。在维生素D相关基因中的CpG中，cg 21201924（RXRA）与25（OH）D相关的p值最低（p=0.0004）。其他22个候选CpG与25（OH）D相关。我们观察到25（OH）D和cg 21201924甲基化之间的相互作用与乳腺癌有关，表明血清25（OH）D浓度高的患者甲基化-乳腺癌风险比更大。我们还观察到其他六种RXRA CpG和CYP 24 A1、CYP 27 B1、NADSYN 1/DHCR 7和VDR中的CpG的统计学显著（p<0.05）相互作用。在子队列的EWAS中，25（OH）D与cg 24350360（EPHX 1; p=3.410-8）、cg 06177555（SPN; p=9.810-8）和cg 13243168（SMARD 2; p=2.910-7）的甲基化相关（q<0.05）。 25（OH）D浓度与几个维生素D相关基因中CpG的DNA甲基化相关，与免疫功能相关基因有潜在联系。维生素D相关基因中CpG的甲基化可能与25（OH）D相互作用，影响乳腺癌的风险。 作为国际乳腺癌联盟的一部分，我们报告了一系列发现，确定了65个与整体乳腺癌风险相关的新遗传基因座; 10个与雌激素受体阴性疾病相关的新遗传基因座，并在遗传预测基因表达的研究中确定了48个表达与风险相关的基因，包括14个新基因座。

Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation. We studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and methylation within a random sample of the cohort ("subcohort"). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH)D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome-wide association study (EWAS) of the association between 25(OH)D and DNA methylation in the subcohort. Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH)D (p=0.0004). Twenty-two other candidate CpGs were associated with 25(OH)D. We observed an interaction between 25(OH)D and methylation at cg21201924 in relation to breast cancer, indicating a larger methylation-breast cancer hazard ratio in those with high serum 25(OH)D concentrations. We also observed statistically significant (p<0.05) interactions for six other RXRA CpGs and CpGs in CYP24A1, CYP27B1, NADSYN1/DHCR7, and VDR. In the EWAS of the subcohort, 25(OH)D was associated (q<0.05) with methylation at cg24350360 (EPHX1; p=3.410-8), cg06177555 (SPN; p=9.810-8), and cg13243168 (SMARCD2; p=2.910-7). 25(OH)D concentrations were associated with DNA methylation of CpGs in several vitamin D-related genes, with potential links to immune function-related genes. Methylation of CpGs in vitamin D-related genes may interact with 25(OH)D to affect the risk of breast cancer. As part of a international consortium on breast cancer we have reported a series of findings identifying 65 new genetic loci associated with overall breast cancer risk; 10 new genetic loci associated with estrogen receptor negative disease, and in a study of genetically-predicted gene expression identify 48 genes whose expression is associated with risk, including 14 novel loci.