He Zihuai, Payne Erin K, Mukherjee Bhramar, Lee Seunggeun, Smith Jennifer A, Ware Erin B, Sánchez Brisa N, Seeman Teresa E, Kardia Sharon L R, Diez Roux Ana V
Department of Biostatistics, University of Michigan, Ann Arbor, United States of America.
Life Sciences Program, Northrop Grumman Health Division, McLean, Virginia, United States of America.
PLoS One. 2015 May 20;10(5):e0126637. doi: 10.1371/journal.pone.0126637. eCollection 2015.
The hormone cortisol is likely to be a key mediator of the stress response that influences multiple physiologic systems that are involved in common chronic disease, including the cardiovascular system, the immune system, and metabolism. In this paper, a candidate gene approach was used to investigate genetic contributions to variability in multiple correlated features of the daily cortisol profile in a sample of European Americans, African Americans, and Hispanic Americans from the Multi-Ethnic Study of Atherosclerosis (MESA). We proposed and applied a new gene-level multiple-phenotype analysis and carried out a meta-analysis to combine the ethnicity specific results. This new analysis, instead of a more routine single marker-single phenotype approach identified a significant association between one gene (ADRB2) and cortisol features (meta-analysis p-value=0.0025), which was not identified by three other commonly used existing analytic strategies: 1. Single marker association tests involving each single cortisol feature separately; 2. Single marker association tests jointly testing for multiple cortisol features; 3. Gene-level association tests separately carried out for each single cortisol feature. The analytic strategies presented consider different hypotheses regarding genotype-phenotype association and imply different costs of multiple testing. The proposed gene-level analysis integrating multiple cortisol features across multiple ethnic groups provides new insights into the gene-cortisol association.
激素皮质醇可能是应激反应的关键介质，它会影响多种参与常见慢性病的生理系统，包括心血管系统、免疫系统和新陈代谢。在本文中，采用候选基因方法，对来自动脉粥样硬化多族裔研究（MESA）的欧裔美国人、非裔美国人和西班牙裔美国人样本中，日常皮质醇水平曲线多个相关特征的变异性进行基因贡献研究。我们提出并应用了一种新的基因水平多表型分析方法，并进行了荟萃分析以整合特定种族的结果。这种新分析方法，而非更常规的单标记-单表型方法，确定了一个基因（ADRB2）与皮质醇特征之间存在显著关联（荟萃分析p值 = 0.0025），而其他三种常用的现有分析策略均未发现这种关联：1. 分别针对每个单一皮质醇特征进行的单标记关联测试；2. 针对多个皮质醇特征联合进行的单标记关联测试；3. 针对每个单一皮质醇特征分别进行的基因水平关联测试。所提出的分析策略考虑了关于基因型-表型关联的不同假设，并暗示了多重检验的不同成本。所提出的整合多个种族群体多个皮质醇特征的基因水平分析，为基因-皮质醇关联提供了新的见解。
