# Lymphocyte CpG methylation changes and brain pathology in Restless Legs Syndrome

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $300,607

## Abstract

Restless leg syndrome (RLS) is a common sensory-motor disorder that has a significant negative impact on the
quality of life for estimated 8 million Americans. Low brain iron, despite the absence of currently existing
systemic iron deficiency, appears to be an important part of the pathology and an important endophenotype of
the disease identifiable with special MRI techniques. One hypothesis is that an initial, early exposure to iron
deficiency (ID) leads to a cell protective response, which, despite the "normalization" of peripheral iron status,
can have a long-term effect on cellular iron homeostasis that sensitive the system to later challenges. Epigenetic
processes provide a mechanism by which environmental factor can influence later life genetic. Thus early
exposure to ID condition may lead to epigenetic changes that set up the risk of developing RLS with later
exposure to environmental factors (e.g., pregnancy, iron deficiency, chronic renal failure, age-related factors)
leading to the phenotypic expression of the underlying genotype. RLS also shows a dominant inheritance
pattern with children from affected mothers having a higher risk than from affected fathers, yet no dominant or
co-dominant gene(s) has been found in GWAS and family studies. In utero exposure to ID with consequential
epigenetic changes may help explain this heritability nature in RLS.
Our primary interest is to identify RLS-relevant epigenetic factors in readily accessible tissues, so later studies
can use them as biomarkers of disease risk and possible indicators of RLS biology and associated medical
conditions. CpG methylation changes in lymphocytes, which have previously been shown to have cellular
changes similar to that seen in RLS autopsy brains, will be used. MRI will be used to measure iron
concentrations in the substantia nigra (SN), which is a well-accepted brain-related endophenotype of the
disease. ID is the most significant and well-recognized environmental factor associated with triggering RLS
symptoms in adults. The prevalence of RLS in the most extreme ID conditions (iron deficiency anemia (IDA))
is 30-40% compared to 5% prevalence of RLS in the general population. A severe iron deficient condition
will be used to delineate two groups with a high degree of discriminative ability to identify disease-relevant or
disease-irrelevant epigenetic biomarkers.
Epigenetic changes, unlike genetic change, are preventable and in some cases reversible. Preventing ID,
therefore, could potentially have the significant impact on RLS development. If a genetic-epigenetic interaction
is identified, then screening for the genetic risk component and applying preventive steps in this group could
dramatic change the public health risk of RLS. A similar option may be indicated for those with a family history
of RLS. The findings would clearly impact the future direction of research in RLS with more of emphasis on
public health risk and prevention of iron deficiency.

## Key facts

- **NIH application ID:** 10169528
- **Project number:** 5R01NS101283-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** CHRISTOPHER J EARLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $300,607
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169528

## Citation

> US National Institutes of Health, RePORTER application 10169528, Lymphocyte CpG methylation changes and brain pathology in Restless Legs Syndrome (5R01NS101283-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10169528. Licensed CC0.

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