Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Thyroid. 2012 Nov;22(11):1181-6. doi: 10.1089/thy.2012.0198. Epub 2012 Oct 19.
Thyroid disorders are associated with an increased risk of cognitive impairment and Alzheimer's disease. Both small vessel disease and neurodegeneration have a role in the pathogenesis of cognitive impairment and Alzheimer's disease. Thyroid hormone receptor alpha (TRα) is the predominant TR in brain. The circadian clock gene REV-ERBα overlaps with the TRα gene and interferes with TRα expression. Limited data are available on the role of the TRα/REV-ERBα locus in small vessel disease and neurodegeneration. We therefore studied genetic variation in the TRα/REV-ERBα locus in relation to brain imaging data, as early markers for small vessel disease and neurodegeneration.
Fifteen polymorphisms, covering the TRα/REV-ERBα locus, were studied in relation to white matter lesion (WML), total brain, and hippocampal volumes in the Rotterdam Study I (RS-I, n=454). Associations that remained significant after multiple testing correction were subsequently studied in an independent population for replication (RS-II, n=607).
No associations with total brain or hippocampal volumes were detected. A haplotype block in REV-ERBα was associated with WML volumes in RS-I. Absence of this haplotype was associated with larger WML volumes in women (0.38%±0.18% [β±SE], p=0.007), but not in men (0.04%±0.11%, p=0.24), which was replicated in RS-II (women: 0.15%±0.05%, p=0.04; men: 0.05%±0.07%, p=0.80). Meta-analysis of the two populations showed that women lacking this haplotype have a 1.9 times larger WML volume (p=0.001).
Our results suggest a role for REV-ERBα in the pathogenesis of WMLs.
甲状腺疾病与认知障碍和阿尔茨海默病的风险增加有关。小血管疾病和神经退行性变在认知障碍和阿尔茨海默病的发病机制中都有作用。甲状腺激素受体 alpha（TRα）是大脑中主要的 TR。昼夜节律基因 REV-ERBα 与 TRα 基因重叠，并干扰 TRα 的表达。关于 TRα/REV-ERBα 基因座在小血管疾病和神经退行性变中的作用，数据有限。因此，我们研究了 TRα/REV-ERBα 基因座的遗传变异与脑成像数据的关系，作为小血管疾病和神经退行性变的早期标志物。
在鹿特丹研究 I（RS-I，n=454）中，研究了涵盖 TRα/REV-ERBα 基因座的 15 个多态性与白质病变（WML）、总脑和海马体积的关系。经过多次测试校正后仍然显著的关联随后在独立人群中进行了复制研究（RS-II，n=607）。
未发现与总脑或海马体积相关的关联。REV-ERBα 中的单倍型块与 RS-I 中的 WML 体积相关。该单倍型的缺失与女性的较大 WML 体积相关（0.38%±0.18%[β±SE]，p=0.007），但与男性无关（0.04%±0.11%，p=0.24），在 RS-II 中得到了复制（女性：0.15%±0.05%，p=0.04；男性：0.05%±0.07%，p=0.80）。两个人群的荟萃分析表明，缺乏这种单倍型的女性 WML 体积增加了 1.9 倍（p=0.001）。
我们的结果表明，REV-ERBα 在 WML 的发病机制中起作用。
