Smith Alicia K, Maloney Elizabeth M, Falkenberg Virginia R, Dimulescu Irina, Rajeevan Mangalathu S
Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, MSG41, Atlanta, GA 30333, USA.
Psychoneuroendocrinology. 2009 May;34(4):597-606. doi: 10.1016/j.psyneuen.2008.10.022. Epub 2008 Dec 10.
Allostatic load (AL) is a theoretical framework that describes the cumulative physiologic effects of adaptation to change or stress throughout the lifespan. AL is operationalized by a composite index of multiple biomarkers. Accordingly, genes, behavior and environment contribute to AL. To determine if individual differences in AL may be influenced by inherent genetic variation, we calculated an allostatic load index (ALI) for 182 Caucasian subjects derived from a population-based study of chronic fatigue syndrome. Nearly 65% of the subjects in this study sample reported fatiguing illness. ALI was calculated based on 11 measures representing metabolic, cardiovascular, inflammatory, hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activities. Subjects were dichotomized into high (ALI > or = 3) or low (ALI < 3) AL groups, and the association between high AL and 129 polymorphisms in 32 genes related to the HPA axis, neurotransmission, inflammation, cardiovascular and metabolic functions were evaluated. Polymorphisms in angiotensin-1 converting enzyme (ACE), corticotropin-releasing hormone receptor 1 (CRHR1), and serotonin receptors (HTR3A and HTR4) were associated with AL (p=0.0007-0.0486), but only one polymorphism, rs4968591, in ACE remained significant after correction for multiple comparisons. The T allele of ACE rs4968591 was more common in subjects with high AL (67.5%) than in subjects with low AL (49.3%) (p=0.0007), and this effect appeared independent of age, sex, body mass index and fatigue status. Additionally, high interleukin-6 (IL-6; p(trend)=0.04), and C-reactive protein (CRP; p(trend)=0.01) levels, as well as low urinary cortisol levels in females (p=0.03) were associated with the T allele, which may result in allele-specific binding of the transcription factor, E2F1. Our results suggest a role for ACE in the bidirectional communication between the central nervous and immune systems in response to stress. Further studies will be needed (a) to replicate the association between AL and ACE polymorphisms in population studies designed to differentiate the effects of sex, age and racial/ethnic background, (b) to evaluate the effect of allele-specific binding of E2F1 at rs4968591, and (c) to examine the role of ACE in the co-regulation of CRP, IL-6 and cortisol.
应激负荷（AL）是一个理论框架，描述了个体在整个生命周期中适应变化或应激的累积生理效应。AL通过多种生物标志物的综合指数来衡量。因此，基因、行为和环境都会影响AL。为了确定AL的个体差异是否可能受到内在基因变异的影响，我们对182名来自一项基于人群的慢性疲劳综合征研究的白种人受试者计算了应激负荷指数（ALI）。在这个研究样本中，近65%的受试者报告患有疲劳性疾病。ALI是基于代表代谢、心血管、炎症、下丘脑-垂体-肾上腺（HPA）轴和交感神经系统（SNS）活动的11项指标计算得出的。受试者被分为高（ALI≥3）或低（ALI<3）应激负荷组，并评估高应激负荷与32个与HPA轴、神经传递、炎症、心血管和代谢功能相关基因中的129个多态性之间的关联。血管紧张素转换酶1（ACE）、促肾上腺皮质激素释放激素受体1（CRHR1）和5-羟色胺受体（HTR3A和HTR4）的多态性与应激负荷相关（p=0.0007 - 0.0486），但在进行多重比较校正后，只有ACE基因中的一个多态性rs4968591仍然显著。ACE rs4968591的T等位基因在高应激负荷受试者中（67.5%）比在低应激负荷受试者中（49.3%）更常见（p=0.0007），并且这种效应似乎独立于年龄、性别、体重指数和疲劳状态。此外，高白细胞介素-6（IL-6；p趋势=0.04）和C反应蛋白（CRP；p趋势=0.01）水平，以及女性低尿皮质醇水平（p=0.03）与T等位基因相关，这可能导致转录因子E2F1的等位基因特异性结合。我们的结果表明ACE在中枢神经系统和免疫系统对应激的双向通信中发挥作用。还需要进一步的研究：（a）在旨在区分性别、年龄和种族/民族背景影响的人群研究中重复应激负荷与ACE多态性之间的关联；（b）评估rs4968591处E2F1的等位基因特异性结合的影响；（c）研究ACE在共同调节CRP、IL-6和皮质醇中的作用。
