MEIS1 variant as a determinant of autonomic imbalance in Restless Legs Syndrome

Jérôme Thireau,Fabrice Bouilloux,Sabine Scholz,Nicolas Molinari,Juliane Winkelmann,Sylvain Richard,Yves Dauvilliers,Frédéric Marmigère,Lucas Torreilles,Charlotte Farah

doi:10.1038/srep46620

Abstract

Restless Legs Syndrome (RLS) is a genetically complex neurological disorder in which overlapping genetic risk factors may contribute to the diversity and heterogeneity of the symptoms. The main goal of the study was to investigate, through analysis of heart rate variability (HRV), whether in RLS patients the MEIS1 polymorphism at risk influences the sympathovagal regulation in different sleep stages. Sixty-four RLS patients with periodic leg movement index above 15 per hour, and 38 controls underwent one night of video-polysomnographic recording. HRV in the frequency- and time- domains was analyzed during nighttime sleep. All RLS patients were genotyped, and homozygotes for rs2300478 in the MEIS1 locus were used for further analysis. Comparison of the sympathovagal pattern of RLS patients to control subjects did not show significant differences after adjustments for confounding factors in frequency-domain analyses, but showed an increased variability during N2 and N3 stages in time-domain analyses in RLS patients. Sorting of RLS patients according to MEIS1 polymorphism reconfirmed the association between MEIS1 and PLMS, and showed a significant increased sympathovagal balance during N3 stage in those homozygotes for the risk allele. RLS patients should be considered differently depending on MEIS1 genotype, some being potentially at risk for cardiovascular disorders.

Highlights

Restless Legs Syndrome (RLS), known as Willis-Ekbom disease, is a genetically complex neurological disorder in which overlapping genetic risk factors contribute to the diversity and heterogeneity of the symptoms[1,2]
This study showed that MEIS1 SNP rs2300478 at risk for RLS influence the sleep stage-dependent sympathovagal balance in RLS patients
Heart Rate Variability (HRV) analysis in the frequency domain revealed a reduction in the parasympathetic activity during slow-wave N3 stage in those homozygotes for the risk allele, whereas time domain and Poincare plot geometry parameters indicated an increased HRV during N2 and N3 stage in RLS patients-independently of MEIS1 genotype

Summary

Introduction

Restless Legs Syndrome (RLS), known as Willis-Ekbom disease, is a genetically complex neurological disorder in which overlapping genetic risk factors contribute to the diversity and heterogeneity of the symptoms[1,2]. The SNPs (Single-Nucleotide Polymorphisms) identified in the eighth intron of the MEIS1 gene suggest that deregulations of mRNA transcription and/or processing participate in the etiology of RLS. A decrease in MEIS1 mRNA and protein has been detected in RLS patients carrying these SNPs11. RLS patients with PLMS may be at risk for heart diseases and hypertension[18]. PLMS episodes occur simultaneously with activation of the SNS as revealed by Heart Rate Variability (HRV) analysis and a rise in blood pressure[22,23,24,25]. The goals of the study were to: 1/compare RLS patients and healthy control subjects through Heart Rate Variability (HRV) analysis of ECG acquired during polysomnographic (PSG) recording; and 2/assess if the MEIS1 SNP rs2300478 influences the sympathovagal regulation according to sleep stages in RLS patients

Objectives

Methods

Results

Conclusion