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Understanding Genetic and Environmental Risk Factors for Multiple Sclerosis

Nearly one million Americans are living with Multiple Sclerosis (MS), according to the National Multiple Sclerosis Society. Although the exact cause of MS remains unclear, it is believed to be an autoimmune disease influenced by both genetic and environmental factors. Researchers continue to study the disease to better understand its causes, improve symptom management, and slow its progression. At Private Health Management (PHM), our team of researchers and clinicians focus on managing serious and complex conditions, including MS. Our experts stay up to date on the latest research and monitor the treatment landscape for clinical trials and emerging therapies. In this article, we offer insights into the genetic and environmental risk factors that contribute to the development and progression of MS.

What is Multiple Sclerosis?
MS is a chronic, progressive disease that causes inflammation in the brain and spinal cord. It happens when the immune system mistakenly attacks the body’s own nerves, damaging the protective coating around them (called myelin).1 This damage, called demyelination, makes it harder for the brain and body to send signals to each other, leading to tingling or numbness, fatigue, blurred vision, imbalance, bladder/bowel issues, slurred speech, and slowed thinking. There are different types of MS, but the most common one is called relapsing-remitting MS, where symptoms come and go over time.

Genetic risk factors for developing MS
Genetics play an important role in a person’s chances of developing MS, but the disease is not inherited in a simple way like some other conditions, so MS cannot be diagnosed with a genetic test. MS is known as a polygenic disease, meaning multiple genetic variants contribute to the risk, but no single variant directly causes it.2 Genetic variants are small differences in DNA sequence that can potentially contribute to certain characteristics, including disease susceptibility. Scientists study these combined genetic factors to estimate how likely someone is to be susceptible to MS. Genetic factors also interact with environmental influences, which can further increase the chances of developing the disease.

Scientists have found that certain genetic variants related to the immune system can increase the risk of developing MS. The most important group of genes linked to MS is called the Major Histocompatibility Complex (MHC), which helps the immune system recognize harmful substances. One specific genetic variant, HLA-DRB1*15:01, is the strongest known genetic risk factor, making MS about three times more likely in people who have it. This variant is common in about 30% of people in the U.S. and Northern Europe and may interact with environmental factors like Vitamin D levels, exposure to the Epstein-Barr virus, and smoking.3-4 In addition, over 200 other genetic variants that influence immune system function have been linked to MS risk.2

MS is three times more common in women than men, though men tend to have more severe disease progression. Researchers believe genetic differences on the X chromosome, along with hormonal influences, may explain why MS affects men and women differently.5

Genetics of disease progression in MS
Genetic factors also play a role in how MS progresses, with some variations linked to more severe symptoms and faster disease progression. Researchers have found that certain genetic variants involved in inflammation can increase disability in MS patients.6 Other variants that affect the nervous system and immune response may lead to a more aggressive form of the disease, especially in people who develop MS later in life.7 Some genetic variants related to blood clotting and metabolism (ex., MTHFR) may also influence disease progression, suggesting a link between these processes and MS.8 Additionally, scientists have identified potential biomarkers that could help predict how the disease will develop. Understanding these genetic influences could help improve future treatments and disease management.

The role of the environment and epigenetics in MS
Epigenetics refers to how the environment can cause changes that affect how the genes work. Unlike genetic changes (mutations), epigenetic changes do not change the DNA itself, but they can influence how genes are turned “on” or “off” and can sometimes be passed down to future generations. These modifications include DNA methylation, which can silence or activate genes, and modifications to proteins called histones, which affect how tightly DNA is packed inside the cell.9,10 Unlike permanent genetic mutations, epigenetic changes can be influenced by the environment and may be reversible. Factors like pollution, smoking, diet, and stress can trigger these changes.11–13

In diseases like MS, epigenetics may play a role in activating the disease in people who already have a genetic risk. Research has shown that epigenetic changes can disrupt the immune system and damage the protective myelin layer around nerves. This can make it harder for nerves to send signals and to repair themselves, leading to worsening symptoms. Scientists have found that micro-RNA, a molecule that helps control gene activity, is different in people with MS.14 Environmental factors such as low vitamin D levels, smoking, toxins, stress, and infections such as Epstein-Barr virus may also trigger harmful epigenetic changes that contribute to nerve damage.15 By studying these changes, researchers hope to predict who is most at risk for MS, improve treatments, and develop new ways to diagnose and manage the disease earlier.

Private Health Management provides comprehensive guidance for people who have signs or symptoms of MS. Our team coordinates testing, arranges for consultations with experts for optimal diagnosis and treatment strategies, and helps to monitor disease progression. In addition, we provide valuable support to people who have been diagnosed with MS and other neurodegenerative diseases.

References

  1. Multiple Sclerosis | National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/multiple-sclerosis.
  2. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility | Science. https://www.science.org/doi/10.1126/science.aav7188.
  3. Handunnetthi, L., Ramagopalan, S. V. & Ebers, G. C. Multiple sclerosis, vitamin D, and HLA-DRB1*15. Neurology 74, 1905–1910 (2010).
  4. The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years – PubMed. https://pubmed.ncbi.nlm.nih.gov/28987266/.
  5. Borziak, K. & Finkelstein, J. X-linked genetic risk factors that promote autoimmunity and dampen remyelination are associated with multiple sclerosis susceptibility. Mult Scler Relat Disord 66, 104065 (2022).
  6. Kallaur, A. P. et al. Genetic, Immune-Inflammatory, and Oxidative Stress Biomarkers as Predictors for Disability and Disease Progression in Multiple Sclerosis. Mol Neurobiol 54, 31–44 (2017).
  7. Lioudyno, V. et al. The effect of galanin gene polymorphism rs948854 on the severity of multiple sclerosis: A significant association with the age of onset. Mult Scler Relat Disord 37, 101439 (2020).
  8. Hadjiagapiou, M. S. et al. Genetic Markers for Thrombophilia and Cardiovascular Disease Associated with Multiple Sclerosis. Biomedicines 10, 2665 (2022).
  9. Principles of DNA methylation and their implications for biology and medicine – PubMed. https://pubmed.ncbi.nlm.nih.gov/30100054/.
  10. Turner, B. M. Histone acetylation and an epigenetic code. Bioessays 22, 836–845 (2000).
  11. Ho, S.-M. et al. Environmental factors, epigenetics, and developmental origin of reproductive disorders. Reprod Toxicol 68, 85–104 (2017).
  12. Vineis, P. et al. Epigenetic memory in response to environmental stressors. FASEB J 31, 2241–2251 (2017).
  13. Gore, A. C. et al. EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev 36, E1–E150 (2015).
  14. Chan, V. S.-F. Epigenetics in Multiple Sclerosis. in Epigenetics in Allergy and Autoimmunity (eds. Chang, C. & Lu, Q.) vol. 1253 309–374 (Springer Singapore, Singapore, 2020).
  15. Manna, I., De Benedittis, S. & Porro, D. A Comprehensive Examination of the Role of Epigenetic Factors in Multiple Sclerosis. Int J Mol Sci 25, 8921 (2024).

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Mariangela

Mariangela Nikolakopoulou, PhD

Associate Research Director

Mariangela Nikolakopoulou is an Associate Research Director at Private Health Management. Her work focuses on neurodegenerative diseases such as Alzheimer’s and Multiple Sclerosis, as well as traumatic brain injury and stroke. At PHM, she identifies and evaluates diagnostic and therapeutic options to meet clients’ unmet needs. With more than 20 years of expertise in neurosciences, Mariangela previously worked as the Principal Investigator at Bionaut Labs. While there, she established a neuroscience laboratory and directed research on medical nanodevices and gene therapies. As an Assistant Professor at USC, she studied the molecular mechanisms of vascular dysfunction in neurological conditions. Mariangela holds a PhD in Neurosciences from Open University in the UK and a Bachelor of Science in Biology from the University of Crete.
Carrie Wynn

Carrie Wynn, MSN, ANP-BC, CCM

Associate Clinical Director

Carrie is an Associate Clinical Director at Private Health Management, working with a clinical team dedicated to managing serious and complex medical conditions. With over 20 years of healthcare experience, including more than a decade as an advanced practice clinician, she has worked across various settings including academic, medical centers, community hospitals, outpatient clinics and telemedicine. Her expertise spans patient care, case management, and program development.