Wang Shengfeng, Huo Dezheng, Kupfer Sonia, Alleyne Dereck, Ogundiran Temidayo O, Ojengbede Oladosu, Zheng Wei, Nathanson Katherine L, Nemesure Barbara, Ambs Stefan, Olopade Olufunmilayo I, Zheng Yonglan
Center for Clinical Cancer Genetics & Global Health, Department of Medicine, University of Chicago, Chicago, IL.
Department of Public Health Sciences, University of Chicago, Chicago, IL.
Int J Cancer. 2018 Jan 1;142(1):36-43. doi: 10.1002/ijc.31038. Epub 2017 Sep 23.
The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, p = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed.
维生素D相关通路已在癌症发生过程中得到评估，但其遗传贡献仍知之甚少。我们使用来自非洲散居人群乳腺癌全基因组关联研究（GWAS）的数据，对维生素D相关通路基因中的单核苷酸多态性（SNP）进行了检测，该研究纳入了3686名参与者（1657例病例）。使用自适应秩截断乘积检验进行通路和基因水平分析。在SNP水平估计优势比（OR）和95%置信区间（CI）。经过严格的Bonferroni校正后，我们在通路、基因或SNP水平均未观察到维生素D通路变异与乳腺癌风险之间存在显著关联。此外，对于维生素D相关性状GWAS报告的信号或维生素D受体（VDR）结合区域内的SNP，均未发现关联。此外，通过孟德尔随机化降低遗传预测的25（OH）D水平与乳腺癌无关（p = 0.23）。然而，乳腺癌与色素合成/代谢通路的关联几乎达到显著水平（通路水平p = 0.08），主要由TYRP1基因中的无义SNP rs41302073驱动，OR为1.54（95% CI = 1.24 - 1.91，p = 0.007）。总之，我们没有发现证据支持非洲裔女性的维生素D状态与乳腺癌风险之间存在关联，这表明维生素D不太可能对乳腺癌发生有显著影响。有趣的是，TYRP1可能通过与维生素D无关的机制与乳腺癌相关，但仍需进一步研究。
