Periodic Leg Movements during Sleep Are Associated with Polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD
Periodic Leg Movements during Sleep Are Associated with Polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD
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DOI：
10.5665/sleep.4006
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发表时间：
2014-09-01
期刊：
影响因子：
5.6
通讯作者：
Mignot, Emmanuel
中科院分区：
文献类型：
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作者：
Moore, Hyatt;Winkelmann, Juliane;Mignot, Emmanuel
研究目标：检查周期性腿部运动 (PLM) 与 6 个已知会增加不宁腿综合征 (RLS) 风险的位点中的 13 个单核苷酸多态性 (SNP) 之间的关联。地点：斯坦福睡眠科学与医学中心和威斯康星大学临床与转化研究所临床研究单位。患者：来自威斯康星州睡眠队列的成年参与者（n = 1,090，平均年龄 = 59.7 岁） （2,394 次观察，2000-2012 年）。设计和干预：使用先前验证的自动检测器来测量 PLMI。测试了 BTBD9、TOX3/BC034767、MEIS1（2 个未连锁位点）、MAP2K5/SKOR1 和 PTPRD 内的 13 个 SNP。使用线性模型并使用 15 PLM/h 截止值按 PLM 类别进行分析。位点的统计显着性是对 6 个位点进行 Bonferroni 校正 (P < 8.3 x 10(-3))。根据邮寄的调查回复，RLS 症状被分为四组：可能、可能、无症状和未知。测量和结果：PLMI >= 15 的患病率为 33%。患有 PLM 的受试者年龄较大，更有可能是男性，并且有更频繁的 RLS 症状、更短的总睡眠时间以及入睡后觉醒的频率更高。除一个位点外，所有位点均发现强关联。使用多变量模型获得 PLMI > 15/h 的最高关联性，包括年龄、性别、睡眠障碍和每个位点的最佳 SNP，产生以下比值比 (OR) 和 P 值：BTBD9 rs3923809(A) OR = 1.65，P = 1.5x10(-8)； TOX3/BC034767 rs3104788(T) OR = 1.35，P = 9.0 x 10(-5)； MEIS1 rs12469063(G) OR = 1.38，P = 2.0 x 10(-4)； MAP2K5/SKOR1 rs6494696(G) OR = 1.24，P = 1.3x10(-2)；和 PTPRD(A) rs1975197 OR = 1.31，P = 6.3x10(-3)。线性回归模型还揭示了 BTBD9、TOX3/BC034767 和 MEIS1 的显着 PLM 效应。 RLS 症状的共变仅适度降低了遗传关联。结论：已证明会增加 RLS 风险的单核苷酸多态性也与增加的 PLM 密切相关，尽管某些位点可能对一种表型的影响更大。
Study Objectives: To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS).Setting: Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research.Patients: Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012).Design and Interventions: A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 x 10(-3)). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response.Measurements and Results: Prevalence of PLMI >= 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5x10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 x 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 x 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3x10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3x10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations.Conclusions: Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.