Shedding light on
Human Genome
Shedding light on Restless Legs Syndrome
Restless via
Legs
Syndrome
the Human
Genome:via the
Pharmacogenomic Implications
David B. Rye
Professor of Neurology
David Rye, MD, PhD
Director, Emory University Program
in Sleepof Neurology
Professor
Atlanta, GA
Director, Emory Healthcare Program in Sleep
RLS Affects Tens of Millions in the
United States alone
RLS is more prevalent than originally
believed1
– RLS affects approximately 10% of the US
adult population, yet often goes undiagnosed2
– Approximately 12 million Americans suffer
from moderate to severe ‘primary’ RLS2,3
1. Hening W. Clin Neurophysiol. 2004;115:1965-1974.
2. Hening W, et al. Sleep Med. 2004;5:237-246.
3. NINDS, NIH; 2001. NIH Publication No. 01-4847.
Burden of RLS is Significant
• Depressed mood (OR = 2.6)
• Stroke & Cardiovascular disease (OR=
2.4-2.5)
• Hypertension (OR = 1.5; *PLMs > 30/hr
OR = 2.3)
Ulfberg J, Nystrom B, Carter N, Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years:
an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001;16:1159-1163.
Winkelman J, Finn L, Young T. Prevalence and correlates of restless legs syndrome in the Wisconsin
sleep cohort. Sleep 2005;28(Abst Suppl):A263-264. – Sleep Medicine 2006-May 30th (epub ahead of print)
*Personal observations; Winkelman et al. (2008) Neurology 70:35-42
RLS
PLM
RLS remains a clinical diagnosis:
IRLSSG/NIH Diagnostic Criteria for RLS
• Urge to move legs, usually accompanied by
uncomfortable leg sensations
• Onset or worsening of symptoms at rest or
inactivity, such as when lying or sitting
• Relief with movement—partial or total relief
from discomfort by walking or stretching
• Worsening of symptoms in the evening and
at night
Allen RP, et al, for the International Restless Legs Syndrome Study Group. Sleep Med. 2003;4:101-119.
Periodic leg movements in
sleep (PLMs) in RLS appear to
exhibit heritability (at least as
much as, if not more than,
sensory symptoms)!
Iron is central to RLS symptomatology
• RLS symptoms occur in > 40% of subjects with
iron deficiency
Akyol et al., Clin Neurol Neurosurg. 2003 Dec;106: 23-7.
• In vivo and in vitro iron depletion in dopamine rich
brain regions of RLS patients
Allen et al., Neurology. 2001 Jan 56: 263-5.
Connor et al., Neurology. 2003 Aug 61: 304-9.
• Iron deficiency adversely affects dopamine
signaling
Allen et al, Sleep Med. 2004 Jul 5:385-91
• Oral and intravenous iron can ameliorate RLS
symptoms.
Earley, Heckler and Allen Sleep Med. 2004 May 5: 231-5.
Iron trafficking appears to be awry in RLS/PLMs – A “leaky” bucket
IRON
RLS Patient
Earley, Heckler and Allen, Sleep Medicine (2005) 6: 301
Treatment Options
• Oral or intravenous iron repletion when iron deficiency
confirmed (9-50% of cases)
• Dopaminergics – 1st line treatment as per American
Sleep Disorders Assoc. Standards of Practice
Committee and the Medical Advisory Board of the RLS
Foundation
• Pramipexole (0.125-0.75mg) – Ropinirole (0.254.0mg) 90-120 minutes before typical symptom onset–
FDA approved for idiopathic, moderate-severe RLS
Off-label:
• Opioids –
• Anticonvulsants – gabapentin
RLS Aggravators
• Alcohol (tanins; GABAAReceptor modulation)
• SNRIs > SSRIs >> SDRIs
• Antidopaminergic medications – e.g.,
metaclopramide; prochlorperazine
(compazine)
• Anti-histamines (e.g., diphenhydramine)
• Over-the-counter sleep aids and cold
remedies (ephedrines)
A genetic-linkage analysis of RLS in Iceland
Funded in part by the Restless Legs Syndrome Foundation in
collaboration with deCODE Genetics, Reykjavik, Iceland
Homogeneity
Excellent genealogic records
Excellent record keeping in health care
Highest literacy rate in the world
Participation in clinical studies is high (80-85%)
4 recently identified gene variants account for at
least 80% of the population attritubable risk for RLS
To everyone’s surprise/dismay:
• None of the implicated genes directly or
indirectly affect iron or dopamine.
• The implicated regions are intronic or
intergenic and suggest regulatory roles.
• The functions are in many cases not well
known.
SNPs associating to RLS are intimately
related to the disease biology:
• Multiple SNPs in at least the BTBD9
and Meis1 genes are related in a dose
dependent fashion to PLMs – bearing
ZERO relationship to RLS rating scales
• Multiple SNPs in the BTBD9 gene are
inversely related in a dose dependent
fashion to low iron stores
• At-risk SNP frequencies in disparate
ethnic groups mirrors the large range
of ethnic differences in RLS prevalence
RLS at-risk variants are COMMON and
considerably impact population risk for RLS
Allele
Frequency
Gene
OR
BTBD9 1.4-2.3 0.73-0.82 (0.656)
0.47-0.61
7x10-7 –
1x10-18
MEIS1
~0.20
1x10-3 –
8x10-16
1x10-2 –
6x10-5
1.7-2.1 0.18-0.21 (0.114)
PAR
MAP2K5 1.3-1.5
0.74-0.78 (0.692)
~0.34
PTPRD
0.17-0.20 (0.13)
<0.10
1.3-1.4
(X.XX) = allele frequency in Icelandic population controls
p value
Homozygous for BTBD9
Younger or Asian
Uremia
Pondering the Genetics Landscape:
Will genotypes correlate with specific phenotypes?
Can genetic testing inform diagnosis and treatment decisions?
What are the downstream molecular networks that effect disease expression?
Pharmacogenics for RLS – targets?
• Treatment stratification
Dopaminergics vs. opioids vs. iron vs. ?
• Complication stratification
Dopaminergic augmentation
Aggravators (e.g., antihistamines;
metaclopramide)
• Predictive Health
End-Stage Renal Disease
Pregnancy
RLS pharmacogenomics - challenges
• RLS genes
Despite high ORs, commonality of at-risk
SNPs necessitates large (600-1000)
sample sizes
Choice of (endo) phenotype
Latent or incipient disease
• Non-RLS genes
Dissecting disease biology
Acknowledgements
Emory Program in Sleep
Dr. Donald Bliwise
Dr. Michael Decker
Dr. Alex Iranzo
Dr. Jeffrey Durmer
Dr. Lynn-Marie Trotti
Dr. Lisa Billars
Dr. Reddiah Mumanenni
Dr. Glenda Keating
Dr. Amanda Freeman
Dr. Tom Genetta
J Max Beck
Gillian Hue
Daniel Miller
Kaniyika Freeman
Emory Dept. of Cell Biology
deCODE Genetics
Dr. S. Sanyal
Dr. Hreinn Stefansson
Dr. KristleifurKristjansson
Emory Dept. of Genetics
Dr. Andrew Hicks
Dr. Steve Warren Dr. Larus Gudmundsson
Dr. Mark Bouzyk
Ingibjorg Eiriksdottir, RN
Dr. Jeffrey Gulcher
Dr. Kari Stefansson
Emory Dept. of Neurology
Dr. Allan Levey
Landspitali
Dr. Salina Waddy
Ami Rosen
Dr. Thordur Sigmundsson
CRIN Staff
Dr. Albert Pal Sigdursson
Emory School of Public Health
Dr. Harland Austin
Funding
RLS Foundation
Arthur L. Williams Jr.
Foundation
Woodruff Health
Sciences