UDP-glucuronosyltransferase genes and gender-differences in lung cancer risk

描述（由申请人提供）：虽然绝大多数肺癌是由吸烟引起的，但大多数终身吸烟者不会患上这种疾病。许多研究表明，女性比男性更容易患肺癌，烟草致癌代谢酶的遗传变异可以解释为什么只有一些吸烟者患肺癌，为什么女性比男性患肺癌的风险更大。我们实验室最近的数据表明，udp -葡萄糖醛基转移酶（UGT2B17）的多态性缺失增加了女性患肺癌的风险（Gallagher等）。, 2007)。这与UGT2B17是强效烟草致癌物的主要解毒剂这一事实相一致，也与包括UGT2B17在内的几种UGT酶的表达受激素调节这一事实相一致。本申请的总体假设是，UGT1A基因的变异增加了肺癌的风险，通过使用单倍型方法综合检测所有UGT1A变异与肺癌的遗传关联，将确定风险等位基因。此外，ugt的激素依赖性调节可能是导致两性肺癌风险差异的重要变量。该项目将使用单倍型来有效和全面地评估UGT1A基因簇中的变异与肺癌风险的关系以及与该疾病的性别特异性关联。在这些独立研究之前，候选人Carla Gallagher博士和她的主要导师，UGT药物遗传学专家Philip Lazarus博士将通过评估UGT1A5来完成LJGT1A基因参与致癌物代谢的研究，UGT1A5是唯一一个尚未被测试的UGT1A基因。在Specific Aim 1中，将确定UGT1A5编码多态性的表达、抗烟草致癌物活性和功能能力。在指导阶段结束后，Gallagher博士将与她的共同导师M. Daniele Fallin博士一起接受单倍型遗传学方面的培训，为独立阶段做准备。在Specific Aim 2中，将进行LJGT1A基因与肺癌风险的单倍型关联研究，并检测性别特异性关联。在特异性目标3中，性别对UGT1A酶的表达和活性的影响将被检查。本研究将有助于识别高危人群，进行针对性肺癌筛查、干预和预防，并可能阐明肺癌风险的性别差异，为设计针对性别的干预措施提供依据。

DESCRIPTION (provided by applicant): Although cigarette smoking causes the vast majority of lung cancers, most lifetime smokers do not develop this disease. Many studies suggest that women have greater susceptibility than men for lung cancer, and genetic variation in tobacco carcinogen-metabolizing enzymes could explain why only some smokers develop lung cancer and why women may be at a greater risk than men. Recent data from our lab has demonstrated that a polymorphic deletion of a UDP-glucuronosyltransferase, UGT2B17, increases risk for lung cancer exclusively in women (Gallagher ef a/., 2007). This is consistent with the fact that UGT2B17 is a major detoxifier of potent tobacco carcinogens and with the fact that expression of several UGT enzymes, including UGT2B17, are regulated by hormones. The overall hypothesis of this application is that variants in UGT1A genes increase risk for lung cancer and that by using a haplotype approach to comprehensively test all UGT1A variation for genetic association with lung cancer, the risk alleles will be identified. Additionally, hormone-dependent regulation of UGTs may be an important variable resulting in differential risk for lung cancer between sexes. This project will use haplotypes to efficiently and comprehensively evaluate variants in the UGT1A gene cluster for involvement in lung cancer risk and for gender-specific associations with this disease. Prior to these independent studies, the candidate, Dr. Carla Gallagher, together with her primary mentor, Dr. Philip Lazarus, an expert in UGT pharmacogenetics, will complete the picture of the involvement of LJGT1A genes in carcinogen metabolism by evaluating UGT1A5, the only UGT1A gene that has yet to be tested for this activity. In Specific Aim 1, expression, activity against tobacco carcinogens, and functional capacity of coding polymorphisms will be determined for UGT1A5. At the completion of the mentored phase, Dr. Gallagher will train with her co-mentor, Dr. M. Daniele Fallin, in haplotype genetics in preparation for the independent phase. In Specific Aim 2, haplotype association studies of LJGT1A genes and lung cancer risk will be performed, and gender-specific associations will be tested. In Specific Aim 3, the effects of gender on expression and activity of UGT1A enzymes will be examined. This study will enable identification of high-risk individuals for targeted lung cancer screening, intervention, and prevention, and may clarify the gender differences in lung cancer risk for design of gender-specific interventions.