How Your Genes May Influence Multiple Sclerosis Treatment: A Closer Look at the ACE Gene and IFN-β Response
Multiple sclerosis (MS) is a complex immune-mediated disease where the immune system attacks the protective sheath (myelin) that covers nerve fibers, leading to inflammation, neurodegeneration, and disability. While treatments like interferon-beta (IFN-β) have brought hope to many, not all patients respond equally—about 30–50% show little to no benefit. This variation has puzzled clinicians and researchers for years, prompting a search for genetic clues that might predict treatment outcomes.
A study published in Pharmacogenetics and Genomics sheds light on a promising lead: a genetic variation in the angiotensin-converting enzyme (ACE) gene may help explain why some MS patients—particularly men—respond poorly to IFN-β therapy.
The ACE Gene and Its Role in MS
The ACE gene is best known for its role in the renin–angiotensin system (RAS), which regulates blood pressure. However, ACE also plays a role in inflammation and immunity—both key elements in MS pathology. Specifically, the enzyme converts angiotensin I into angiotensin II, a molecule that can trigger inflammation and potentially damage the central nervous system (CNS).
Researchers have long known about a common genetic variant in the ACE gene called the insertion/deletion (I/D) polymorphism, where people can have either:
II genotype (two copies of the insertion),
ID genotype (one insertion, one deletion),
DD genotype (two deletions).
The DD genotype is associated with higher ACE activity—and possibly with a more aggressive inflammatory profile.
Study Design: Looking at the Genetic Landscape
This preliminary study investigated whether the ACE I/D polymorphism influences how patients respond to IFN-β. Researchers followed 275 Croatian and Slovenian MS patients (211 women and 64 men) over two years of IFN-β treatment. They classified patients as:
Responders (Rs): No disease progression or relapses.
Nonresponders (NRs): One or more relapses and worsening disability.
Using genetic testing and statistical analysis, the study aimed to find links between the ACE I/D genotypes and treatment response.
Key Findings: Men, Genes, and Treatment Resistance
Men with the DD genotype were significantly more likely to be nonresponders to IFN-β.
In men, the D allele was linked to more than twice the odds of poor response (Odds Ratio: 2.43).
The DD genotype alone accounted for about 13.2% of the variability in IFN-β treatment response in men.
In contrast, women showed no significant association between ACE genotype and treatment response.
A higher relapse rate before starting IFN-β also predicted a poorer response, both in men and women. When combined with ACE genotype data, this explained ~26.7% of treatment variability in men.
Why Might This Happen?
The link between the ACE-DD genotype and high ACE levels could mean a more intense inflammatory environment in the CNS—one that IFN-β can't effectively counter. Given that angiotensin II can disrupt the blood-brain barrier and activate immune cells in the brain, men with this genotype may have a biological predisposition to resist IFN-β’s immunomodulatory effects.
Interestingly, previous studies have also linked the ACE-DD genotype to an increased risk of developing MS, particularly in men. So, this genetic variant may influence both the likelihood of getting MS and the effectiveness of its treatment.
What Does This Mean for MS Patients?
This study underscores the importance of personalized medicine. If these findings are confirmed in larger studies, genetic testing for the ACE I/D polymorphism could one day help:
Predict whether IFN-β will be effective for a given patient.
Guide clinicians toward more personalized treatment plans from the outset.
Reduce time lost on ineffective therapies and improve patient outcomes.
However, it's important to remember that this is a preliminary study, and many other genes and environmental factors also influence MS and its treatment. The findings do not yet warrant changes to clinical practice, but they pave the way for future research.
Conclusion: A Step Toward Tailored Treatment
The discovery of a link between the ACE gene and IFN-β treatment response in men is an exciting development in MS research. It highlights the complexity of autoimmune diseases and the need to consider genetic individuality in treatment decisions. While we’re still far from fully personalized MS therapies, studies like this bring us one step closer to that goal.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Ristić et al. (2017). Angiotensin-converting enzyme insertion/deletion gene polymorphism and interferon-β treatment response in multiple sclerosis patients: a preliminary report. Pharmacogenetics and Genomics, 27:232–235. DOI: 10.1097/FPC.0000000000000283
