Biological and Environmental modifiers of Vitamin D3 and Prostate Cancer Risk

描述(由申请人提供)：前列腺癌(PCA)的差异是由遗传易感性、个体风险因素和环境因素的复杂相互作用引起的。 前列腺癌是所有男性的第二大死因；然而，非裔美国人(AA)的前列腺癌死亡率是美国所有种族/民族中最高的。这一死亡率差异占AA和欧洲裔美国人(EA)男性总体癌症死亡率差异的44%。因此，迫切需要探索导致这种差异的病因途径。不幸的是，前列腺癌唯一公认的危险因素(年龄、种族和家族史)是不可改变的。然而，最近的研究发现，低水平的维生素D与增加PCa的风险有关，在多项研究中，维生素D的治疗减缓了PCa的疾病进展。这些研究支持这样一种假设，即维生素D缺乏会增加前列腺癌的风险，并且维生素D是一种潜在的化学预防和治疗药物。虽然遗传和环境因素，包括常见的低渗透等位基因、饮食、体重指数(BMI)和维生素D水平可能会影响风险，但它们的重要性和多重联合影响尚不清楚。存在大量数据来支持关键的 维生素D3[25(OH)维生素D]在前列腺癌风险中的作用。然而，很难确定它的重要性，主要是因为维生素D是在皮肤中合成的，血清水平受到肤色、遗传血统、年龄、BMI和环境因素(如阳光照射和饮食)的强烈影响。该项目的目标是通过对2,000名AA和2,000名EA男性的研究，探讨血清维生素D、紫外线照射、肤色、年龄、体重指数以及维生素D合成、代谢和信号转导相关基因对前列腺癌和侵袭性前列腺癌风险的影响。40-79岁的男性将从芝加哥医院财团招募，其中包括伊利诺伊大学芝加哥医院系统、芝加哥大学医疗中心、西北纪念医院、约翰·H·斯特罗格·库克县医院和杰西·布朗退伍军人事务医疗中心。这个项目将提高我们对维生素D在前列腺癌易感性中的作用的理解，特别是在非裔美国人中，如果AA中较低的维生素D水平解释了AA和EA之间的PCa发病率和死亡率差异的一部分。更重要的是，鉴于UVR和饮食是容易修改的一般环境暴露，了解它们的影响可能会对健康产生广泛的影响。 公共卫生相关性：维生素D已被证明可诱导前列腺细胞分化，抑制前列腺癌细胞系的生长并诱导其凋亡。有流行病学证据表明维生素D状态与乳腺癌、结肠癌和前列腺癌有关。前瞻性研究一直缺乏，在文献中也没有确定的结果。值得注意的是，这些研究缺乏大量非洲血统的男性，他们可能患有侵袭性前列腺癌，并且更缺乏维生素D。此外，这些研究也没有考虑维生素D合成和代谢途径中维生素D水平、阳光照射、肤色和基因遗传变异之间的相互作用。在这里，我们将提出一项前瞻性研究，研究40-79岁的非裔美国人和欧洲裔美国人的血清维生素D(25-OHD)水平和前列腺癌风险。这项研究将在芝加哥地区的五家机构进行，它们是伊利诺伊大学芝加哥医院系统、芝加哥大学医疗中心、西北纪念医院、约翰·H·斯特罗格·库克县医院和芝加哥的杰西·布朗退伍军人事务医疗中心。

DESCRIPTION (provided by applicant): Disparities in prostate cancer (Pca) are caused by complex interactions of genetic susceptibility, individual risk factors, and environmental factors. Pca is the second leading cause of death among all men; however African American (AA) men have the highest mortality rate of Pca of any racial/ethnic group in the U.S. This difference in mortality accounts for 44% of the overall cancer mortality disparity between AA and European-American (EA) men. Thus, there is a critical need to explore the etiologic pathways that contribute to this disparity. Unfortunately, the only well-established risk factors (age, race and family history) for Pca are non-modifiable. However recent studies have found low levels of vitamin D have been associated with increased Pca risk, and treatment with vitamin D has reduced Pca disease progression in multiple studies. These studies support the hypothesis that vitamin D deficiency increases the risk of Pca and that vitamin D is a potential chemopreventive and therapeutic agent. Although genetic and environmental factors including common low penetrant alleles, diet, body mass index (BMI), and vitamin D levels may affect risk, their significance and multiple joint effects are unclear. Extensive data exists in support of a critical role for Vitamin D3 [25(OH) vitamin D] on Pca risk. However, it is difficult to determine its importance mainly because Vitamin D is synthesized in the skin, and serum levels are strongly influenced by skin color, genetic ancestry, age, BMI, and environmental factors such as sunlight exposure and diet. The goal of this project is to explore the effects of serum Vitamin D, UVR exposure, skin color, age, BMI, and genes involved in Vitamin D synthesis, metabolism and signaling on Pca and aggressive Pca risk in a study of 2,000 AA and 2,000 EA men. Men aged 40-79 will be recruited from a consortium of Chicago hospitals including, the University Illinois a Chicago Hospital System, University of Chicago Medical Center, Northwestern Memorial Hospital, John H. Stroger Cook County Hospital, and the Jesse Brown Veteran Affairs Medical Center. This project will improve our understanding of the role Vitamin D plays on prostate cancer susceptibility, specifically among African Americans, and if lower vitamin D levels in AAs account for a portion of the disparity in Pca incidence and mortality between AAs and EAs. More importantly, given that UVR and diet are general environmental exposures that can be easily modified, understanding their impact may have broad health implications. PUBLIC HEALTH RELEVANCE: Vitamin D has been shown to induce differentiation of prostate cells and to inhibit growth and induce apoptosis in prostate cancer cell lines. There has been epidemiologic evidence linking vitamin D status to breast, colon and prostate cancer. Prospective studies have been lacking and among the literature there have been inconclusive results. Notably, these studies are lacking in numbers of men of African ancestry who are likely to have aggressive prostate cancer and to be more vitamin D deficient. Also the studies fail to look at the interaction of vitamin D level, sun exposure, skin color, and genetic variation in genes in the vitamin D synthesis and metabolism pathway. Here we will propose a prospective study of serum vitamin D (25-OH D) levels and prostate cancer risk among African American and European American men aged 40-79. The study will be conducted at five Chicago area institutions, the University Illinois at Chicago Hospital System, University of Chicago Medical Center, Northwestern Memorial Hospital, John H. Stroger Cook County Hospital, and the Jesse Brown Veteran Affairs Medical Center in Chicago.