NEW YORK (Reuters Health) - In amyotrophic lateral sclerosis (ALS), factors such as body mass index (BMI), alcohol intake, high-density lipoprotein (HDL) cholesterol, and white blood cell (WBC) proportions may play a causal role, a genome-wide DNA methylation study suggests.
"Our analyses provide converging evidence that the epigenetic alterations in ALS can be linked to biological processes involved in metabolism, cholesterol and immunity," Dr. Jan Veldink of University Medical Center Utrecht in the Netherlands told Reuters Health by email.
"We see a lot of methylation differences between ALS patients and controls, and also a lot of methylation differences related to disease progression, but these differences are really small per individual patient," he noted. "As a consequence, we cannot derive clear recommendations for patients to be used in daily clinical practice."
DNA methylation patterns can serve as proxies of past exposures and disease progression and also provide a potential mechanism that mediates genetic or environmental risk, Dr. Veldink and colleagues explain in Science Translational Medicine.
Analyzing blood samples from 6,763 patients and 2,943 controls, they identified 45 DNA methylation sites related to ALS in 42 genes that are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity.
Then they tested 39 DNA methylation patterns as proxies for ALS risk factors and found, as Dr. Veldink indicated, that HDL cholesterol, BMI, white blood cell proportions, and alcohol intake were independently associated with ALS.
When they integrated the results with their latest genome-wide association study, they found that cholesterol biosynthesis was potentially causally related to ALS.
Further investigations showed an association between five of the DNA methylation sites and patient survival rates, suggesting that these sites might be indicators of underlying disease processes that could potentially be amenable to therapeutic interventions.
Dr. John Novak, Director, OhioHealth ALS Clinic and Medical Director for Neurology, Grant Medical Center, both in Columbus, commented in an email to Reuters Health, "Any research that helps us to discover what starts ALS and can develop treatments that address initial derangements, as opposed to downstream affects, will be important to have in our treatment regimens."
"This study is also important as it looks at ALS as a systemic disease with potential metabolic and immune components," he said. "These findings may help to shine light on new avenues of research or treatments. While the authors admit they could not study the methylation patterns in neurons and focused on changes in blood, they did see reliable changes in ALS patients that point toward a system-wide disease process."
"The main caveat with this study, and is mentioned by the authors as well, is the findings may not necessarily correlate with causing ALS but could be a consequence of ALS," he added. "This may still help develop treatments but at this point is too early to say these changes are causative."
Dr. Zhenghong Gao, a mechanical engineering research scientist at The University of Texas at Dallas with a grant to explore CRISPR treatment for ALS, also commented by email. "This study used blood samples. It will be interesting to evaluate whether a similar DNA methylation pattern/association exists in cerebrospinal fluid samples."
"DNA methylation patterns may have associations with detection, stage, and progression," he said. "I am wondering whether the information uncovered by this study can lay out the foundation for developing a sensitive platform for the early detection of ALS. Early detection will be helpful for planning treatment and improving the quality of life of patients."
"More studies will need to investigate the value of a lifestyle change to patients at risk," he concluded.
SOURCE: https://bit.ly/3CaY1Ra Science Translational Medicine, online February 23, 2022.
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