MEIS1 and BTBD9: genetic association with restless leg syndrome in end stage renal disease

Background Restless legs syndrome (RLS) is a sleep related movement disorder that occurs both in an idiopathic form and in symptomatic varieties. RLS is a frequent and distressing comorbidity in end stage renal disease (ESRD). For idiopathic RLS (iRLS), genetic risk factors have been identified, but their role in RLS in ESRD has not been investigated yet. Therefore, a case–control association study of these variants in ESRD patients was performed. Methods The study genotyped 10 iRLS associated variants at four loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, and PTPRD, in two independent case–control samples from Germany and Greece using multiplex PCR and MALDI-TOF (matrix assisted laser desorption/ionisation time-of-flight) mass spectrometry. Statistical analysis was performed as logistic regression with age and gender as covariates. For the combined analysis a Cochran–Mantel–Haenszel test was applied. Results The study included 200 RLS-positive and 443 RLS-negative ESRD patients in the German sample, and 141 and 393 patients, respectively, in the Greek sample. In the German sample, variants in MEIS1 and BTBD9 were associated with RLS in ESRD (Pnom≤0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (Pnom≤0.08, ORs 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (Pcorrected=0.0013, OR 1.47). Conclusions This is the first demonstration of a genetic influence on RLS in ESRD patients with BTBD9 being significantly associated. The extent of the genetic predisposition could vary between different subgroups of RLS in ESRD.

[1]  G. Plazzi,et al.  Restless legs syndrome enhances cardiovascular risk and mortality in patients with end-stage kidney disease undergoing long-term haemodialysis treatment. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  C. Fox,et al.  Genetics of Chronic Kidney Disease , 2010, Nephron Clinical Practice.

[3]  P. F. D. de Bruin,et al.  Restless legs syndrome in end-stage renal disease: Clinical characteristics and associated comorbidities. , 2010, Sleep medicine.

[4]  C. Gieger,et al.  Replication of restless legs syndrome loci in three European populations , 2009, Journal of Medical Genetics.

[5]  C. Gieger,et al.  PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome , 2008, Nature Genetics.

[6]  M. Matsuura,et al.  Clinical characteristics of restless legs syndrome in end‐stage renal failure and idiopathic RLS patients , 2008, Movement disorders : official journal of the Movement Disorder Society.

[7]  Lisa M. Schwartz,et al.  A genetic risk factor for periodic limb movements in sleep. , 2008, The New England journal of medicine.

[8]  S. Konitsiotis,et al.  Low RLS prevalence and awareness in central Greece: an epidemiological survey , 2007, European journal of neurology.

[9]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[10]  Kari Stefansson,et al.  A genetic risk factor for periodic limb movements in sleep. , 2007, The New England journal of medicine.

[11]  Christian Gieger,et al.  Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions , 2007, Nature Genetics.

[12]  G. Abecasis,et al.  Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies , 2006, Nature Genetics.

[13]  D. Kavanagh,et al.  Risk Factors for Restless Legs Syndrome in Dialysis Patients , 2005, Nephron Clinical Practice.

[14]  M. Molnar,et al.  Restless Legs Syndrome in patients after renal transplantation. , 2005, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[15]  U. John,et al.  Sex and the risk of restless legs syndrome in the general population. , 2004, Archives of internal medicine.

[16]  M. Nangaku,et al.  Clinical and psychological aspects of restless legs syndrome in uremic patients on hemodialysis. , 2003, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[17]  Richard P Allen,et al.  Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. , 2003, Sleep medicine.

[18]  Qu Huiqi,et al.  Restless Legs Syndrome (RLS) in Uremic Patients Is Related to the Frequency of Hemodialysis Sessions , 2000, Nephron.

[19]  M. Dichgans,et al.  Clinical characteristics and frequency of the hereditary restless legs syndrome in a population of 300 patients. , 2000, Sleep.

[20]  T. Young,et al.  Epidemiology of restless legs symptoms in adults. , 2000, Archives of internal medicine.

[21]  U. Keil,et al.  Prevalence and risk factors of RLS in an elderly population , 2000, Neurology.

[22]  U. Keil,et al.  Prevalence and risk factors of RLS in an elderly population , 2000, Neurology.

[23]  W. Oertel,et al.  Polysomnographic sleep measures in patients with uremic and idiopathic restless legs syndrome , 1998, Movement disorders : official journal of the Movement Disorder Society.

[24]  W. Oertel,et al.  Clinical and biochemical findings in uremic patients with and without restless legs syndrome. , 1998, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[25]  P. Lespérance,et al.  Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: A study of 133 patients diagnosed with new standard criteria , 1997, Movement disorders : official journal of the Movement Disorder Society.

[26]  G. Chertow,et al.  Restless legs syndrome in end-stage renal disease. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[27]  W. Oertel,et al.  Genetics of restless legs syndrome (RLS): State‐of‐the‐art and future directions , 2007, Movement disorders : official journal of the Movement Disorder Society.

[28]  G. Gigli,et al.  Sleep disorders in patients with end-stage renal disease undergoing dialysis therapy. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.