Rajeevan M S, Smith A K, Dimulescu I, Unger E R, Vernon S D, Heim C, Reeves W C
Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
Genes Brain Behav. 2007 Mar;6(2):167-76. doi: 10.1111/j.1601-183X.2006.00244.x.
Chronic fatigue syndrome (CFS) is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association of CFS with deregulation of immune functions and hypothalamic-pituitary-adrenal (HPA) axis activity. In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis. There were 137 study participants (40 with CFS, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS. Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS. We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the Centers for Disease Control Symptom Inventory). Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05-6.45) to 3.00 (CI 1.12-8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS. These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5' region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.
慢性疲劳综合征（CFS）是一个病因不明的重大公共卫生问题，其病理生理学尚未阐明，且没有特征性的体征或实验室异常。一些研究表明，CFS与免疫功能失调和下丘脑 - 垂体 - 肾上腺（HPA）轴活动有关。在本研究中，我们检测了糖皮质激素受体基因（NR3C1）序列变异与CFS的关联，因为NR3C1是HPA轴的主要效应器。有137名研究参与者（40例CFS患者、55例症状不足或疲劳者，称为ISF，以及42例非疲劳对照），他们来自堪萨斯州威奇托市的普通人群，经过临床评估和识别。对NR3C1中的9个单核苷酸多态性（SNP）进行了多态性和单倍型与CFS关联的检测。与非疲劳（NF）受试者相比，我们观察到多个SNP与慢性疲劳相关（P < 0.05），并发现与功能损害的定量评估（通过SF - 36）、疲劳（通过多维疲劳量表）和症状（通过疾病控制中心症状量表评估）有类似关联。所有相关SNP主要等位基因的纯合子受试者患CFS的风险增加，优势比范围为2.61（CI 1.05 - 6.45）至3.00（CI 1.12 - 8.05）。五个SNP覆盖约80 kb的区域，在CFS中显示出高度连锁不平衡（LD），但在ISF至NF受试者中LD逐渐下降。此外，对处于LD区域的单倍型分析确定了两个具有相反等位基因的相关单倍型：一个具有保护作用，另一个赋予CFS风险。这些结果表明NR3C1是慢性疲劳的潜在介导因子，并暗示NR3C1 5'区域的变异可能是HPA轴调节改变和CFS行为特征表现的一种可能机制。
