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。我们研究了血清维生素D、DNA甲基化和乳腺癌之间的关系，使用非西班牙裔白人妇女的病例队列样本（1070例，亚队列1277例）。在我们的初步分析中，我们使用稳健线性回归来检验随机队列（“亚队列”）样本中血清25-羟基维生素D （25(OH)D）与甲基化之间的关系。我们重点研究了7个维生素d相关基因或其附近的198个CpGs。对于这198个候选CpG基因座，我们还研究了甲基化和25(OH)D之间的增殖相互作用如何与乳腺癌风险相关。这是使用Cox比例风险模型和全病例队列样本完成的。此外，我们在亚队列中进行了25(OH)D与DNA甲基化之间关系的探索性全表观基因组关联研究（EWAS）。在维生素D相关基因的CpGs中，cg21201924 （RXRA）与25(OH)D相关的p值最低（p=0.0004）。另外22个候选CpGs与25(OH)D相关。我们观察到与乳腺癌相关的25(OH)D和甲基化在cg21201924之间的相互作用，表明在血清25(OH)D浓度高的人群中，甲基化-乳腺癌的风险比更大。我们还观察到其他六种RXRA CpGs与CYP24A1、CYP27B1、NADSYN1/DHCR7和VDR的CpGs相互作用具有统计学意义（p<0.05）。在该亚队列的EWAS中，25(OH)D与cg24350360 （EPHX1; p=3.410-8）、cg06177555 （SPN; p=9.810-8）和cg13243168 （SMARCD2; p=2.910-7）位点的甲基化相关（q<0.05）。25(OH)D浓度与几种维生素D相关基因中CpGs的DNA甲基化有关，与免疫功能相关基因有潜在联系。维生素D相关基因中CpGs的甲基化可能与25(OH)D相互作用，从而影响乳腺癌的风险。

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.