Multiethnic Genome Scan of Metabolic Phenotypes

代谢表型的多种族基因组扫描

基本信息

批准号：
7786633
负责人：
LOIC LE MARCHAND
金额：
$ 103.01万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7786633
关键词：
1-Butanol 2-butenal Accounting Acids Acrolein Affect African African American Age Alleles American Aromatic Polycyclic Hydrocarbons Asians Behavioral Genetics Benzene Exposure Biological Biological Markers Butanones Cancer Etiology Candidate Disease Gene Carcinogen exposure Carcinogens Cessation of life Cigarette Cohort Studies Collaborations Cotinine DNA Repair DNA Repair Gene DNA Repair Pathway Data Diet Disease Dose Drug Metabolic Detoxication Ensure Environmental Risk Factor Ethnic Origin Ethnic group Ethylene Oxide European Exposure to Female Genes Genetic Genetic Epistasis Genetic Markers Genetic Variation Genome Scan Genotype Glucuronides Glues Haplotypes Hawaiian population Incidence Inherited Japanese American Laboratories Latino Lead Lung Malignant neoplasm of lung Measures Metabolic Metabolic Activation Metabolism Methods Minority Groups Modification Nicotine Nicotine Dependence Nicotinic Receptors Patient Self-Report Phenotype Population Predisposition Publishing Race Research Personnel Risk Risk Factors Role Sampling Single Nucleotide Polymorphism Smoke Smoker Smoking Smoking Status Sum Testing Time Tobacco Tobacco smoke Tobacco-Associated Carcinogen Urine Variant base cancer risk cigarette smoking cohort ethnic difference genetic variant genome wide association study genome-wide high risk hydroxycotinine lung cancer prevention male mortality phenanthrene prevent racial and ethnic racial/ethnic difference sex smoking cessation tobacco control urinary

项目摘要

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.

肺癌是全球死亡率的主要原因。虽然烟草控制是最好的方法防止这种疾病，几乎没有迹象表明在美国，吸烟率会进一步降低证明美国种族/族裔少数民族在肺癌风险中存在2-5倍的差异即使考虑到自我报告的剂量（每天香烟）和期间。夏威夷原住民和非裔美国人患肺癌的风险明显高于欧洲美国人的风险明显高于日裔美国人和拉丁美洲人。我们假设这些差异与影响尼古丁和烟草烟雾毒素的内部剂量和代谢的常见遗传变异有关，以及/或DNA修复。我们与实验室研究人员在此POI上合作获得的初步数据表明，作用在几种代谢和/或DNA修复途径上的遗传因素和行为因素的结合可能会解释观察到的风险中观察到的种族差异。我们建议进行一项全基因组关联研究（GWAS），以全面评估遗传变异在预测11种生物标志物表型（通过核心B）中与烟草致癌和尼古丁暴露有关的11种生物标志物表型（通过核心B），以及2,250名夏威夷本地人，非裔美国人，欧洲，美洲，拉丁裔和日裔美国人烟民中的2,250名本地人使用多个研究中的生物标志物表型。我们预计，常见的遗传变异将有助于更好地评估一个人的实际暴露水平（与香烟相比），并能够代谢烟草癌，从而更好地预测患肺癌的风险。我们还期望潜在的因果变异在肺癌高风险的种族/种族种群中更为普遍。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修复基因中的变体，以与MEC中1,448例事件病例和1,448个匹配的对照中的肺癌发病率相关联。这些研究的结果将提供有关尼古丁和烟草癌及其内部剂量和代谢的生物决定因素及其代谢的重要信息。与肺癌风险的关系在美国/种族少数群体中。