A genetic risk factor for periodic limb movements in sleep
A genetic risk factor for periodic limb movements in sleep
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DOI：
10.1056/nejmoa072743
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发表时间：
2007-08-16
影响因子：
158.5
通讯作者：
Stefansson, Kari
中科院分区：
文献类型：
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作者：
Stefansson, Hreinn;Rye, David B.;Stefansson, Kari
背景：不宁腿综合征(RLS)是一种常见的神经系统疾病，其特征是无法抗拒移动双腿的冲动。这是睡眠障碍的一个主要原因。在大多数RLS患者中，睡眠中的周期性肢体运动是可以检测到的，并代表了一种客观的生理指标。方法：为了寻找与RLS相关的序列变异，我们进行了全基因组关联研究和两项复制研究。为了最大限度地减少表型的异质性，我们将重点放在了客观记录睡眠中周期性肢体运动的RLS患者身上。我们测量了血清铁蛋白水平，因为铁缺乏与RLS的发病机制有关。结果：在冰岛发现的RLS患者和睡眠中周期性肢体运动的样本中，我们观察到全基因组与染色体6p21.2上BTBD9内含子的一个常见变异显著相关(优势比，1.8；P=2×10(sup-9))。这种关联在第二个冰岛样本(优势比为1.8；P=4x10(sup-4))和一个美国样本(优势比为1.5；P=4x10(sup-3))中重复。在这种变异情况下，伴有周期性肢体活动的RLS的人群归因风险约为50%。在没有RLS的睡眠中变异的肢体运动和周期性肢体运动之间的关联(而没有RLS的RLS没有这种关联)表明我们已经确定了睡眠中周期性肢体运动的基因决定因素(优势比，1.9；P=1 x 10(sup-17))。高危变异的每个等位基因的血清铁蛋白水平降低了13%(95%可信区间，5到20；P=0.002)。结论：我们发现了一种与睡眠中周期性肢体运动易感性相关的变异。该变异与铁储存呈负相关，这与怀疑铁缺乏参与了疾病的发病机制是一致的。
Background: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. Methods: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. Results: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2 x 10(sup -9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4 x 10(sup -4)) and a U.S. sample (odds ratio, 1.5; P=4 x 10(sup -3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1 x 10(sup -17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). Conclusions: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.