Multiethnic Genome Scan of Metabolic Phenotypes

肺癌是世界范围内导致死亡的主要原因。尽管控制烟草是最好的方法 为了预防这种疾病，几乎没有迹象表明美国的吸烟率会进一步下降。 有记录表明，美国少数族裔之间患肺癌的风险存在2至5倍的差异 与吸烟有关，即使在考虑到自我报告的剂量(每天吸烟)和 持续时间。夏威夷原住民和非裔美国人患肺癌的风险明显高于欧洲人 反过来，他们的风险明显高于日裔美国人和拉美裔美国人。我们假设这些差异与常见的遗传变异有关，这些变异影响尼古丁和烟草烟雾致癌物的内部剂量和新陈代谢，以及/或DNA修复。我们与实验室研究人员就这一POI合作获得的初步数据表明，作用于几个代谢和/或DNA修复途径的遗传和行为因素的组合可能解释了观察到的风险种族差异。我们建议在多种族队列研究中，在2,250名夏威夷原住民、非裔美国人、欧洲裔美国人、拉美裔和日本裔美国吸烟者中，利用储存的生物谱系，全面评估遗传变异在预测与烟草致癌物质和尼古丁暴露和代谢相关的11种生物标记物表型中的作用。我们希望常见的遗传变异有助于更好地评估一个人的实际暴露水平(与香烟/天相比)和代谢烟草致癌物的能力，从而更好地预测患肺癌的风险。我们还预计潜在的因果变异在肺癌高危民族/种族人群中更常见。最后，作为该项目的一部分，我们将测试与这些表型相关的遗传变异，以及DNA修复基因的变异，以确定与肺癌发病率的关联，在MEC的1,448例病例和1,448名匹配对照中，相同的五个民族。这些研究的结果将提供关于尼古丁和烟草致癌物及其代谢的生物决定因素的重要信息。 美国少数族裔与肺癌风险的关系。

Lung cancer is the leading cause of mortality worldwide. Although tobacco control is the best method for preventing this disease, there is little indication that smoking rates will decrease much further in the U.S. We documented that there exist 2-to-5-fold differences among US racial/ethnic minorities in the risk of lung cancer associated with cigarette smoking, even after taking into account self-reported dose (cigarettes per day) and duration. Native Hawaiians and African Americans have a significantly higher risk for lung cancer than European Americans, who in turn have a significantly higher risk than Japanese Americans and Latinos. We hypothesize that these differences are related to common genetic variants that affect internal dose and metabolism of nicotine and tobacco smoke carcinogens, and/or DNA repair. Our preliminary data obtained collaboratively with the laboratory investigators on this POI suggest that a combination of genetic and behavioral factors acting on several metabolic and/or DNA repair pathways are likely to explain the observed ethnic differences in risk. We propose to conduct a genome-wide association study (GWAS) to comprehensively assess the role of genetic variation in predicting 11 biomarker phenotypes (measured by Core B) related to tobacco carcinogen and nicotine exposure and metabolism among 2,250 Native Hawaiian, African American, European American, Latino and Japanese American smokers in the Multiethnic Cohort study, using stored biospecimens. We expect common inherited variation to assist in better assessing one's actual exposure level (as compared to cigarettes/day) and ability to metabolize tobacco carcinogens and, thus, in better predicting risk of developing lung cancer. We also expect the underlying causal variants to be more common in ethnic/racial populations at high risk for lung cancer. Finally, as part of this project, we will test the genetic variants associated with these phenotypes, as well as variants in DNA repair genes, for association with lung cancer incidence among 1,448 incident cases and 1,448 matched controls ofthe same five ethnic groups in the MEC. The results of these studies will provide important information on the biological determinants of internal dose and metabolism of nicotine and tobacco carcinogens and their relationships to lung cancer risk in U.S. ethnic/racial minorities.