Beyond the "MS Gene": How Genetic Variations Can Tip the Scales
If you've ever thought about the genetics of a complex disease like Multiple Sclerosis (MS), you might imagine scientists hunting for a single "MS gene"—one big genetic culprit responsible for the illness.
The reality, as researchers are discovering, is far more complex and fascinating.
MS is a chronic inflammatory disease where the body's own immune system mistakenly attacks the protective covering of nerves in the central nervous system. We've known for a long time that its causes are a complicated mix of environmental factors and genetics. But even after finding many genes linked to MS, scientists still couldn't explain all of the heritability they saw in families.
This "missing heritability" has led researchers to look in a new, exciting place: epigenetics.
Think of your DNA as a massive cookbook. Epigenetics is like the collection of sticky notes and highlights that tell your cells which recipes (genes) to use, when to use them, and how much to make. A recent study by Dr. Seyede Zahra Nazari Mehrabani and colleagues decided to look for genetic variation in the genes that write or read these epigenetic notes.
Their findings give us a powerful glimpse into how tiny, subtle variations in our DNA can work together to increase or decrease a person's risk for MS.
The Hunt for Clues: What Did They Look For?
The researchers focused on five specific, tiny variations in the genetic code, known as Single Nucleotide Polymorphisms (SNPs). A SNP is simply a spot in our DNA where some people might have one letter (like a 'G') while others have another (like a 'T').
They didn't pick these SNPs at random. They targeted genes that are involved in the body's epigenetic "dimmer switches":
SHMT1: A gene that's crucial for DNA methylation—one of the body's main ways of putting those "sticky notes" on genes to silence them. It's also involved in DNA synthesis and repair.
MAZ: This gene creates a protein that responds to inflammation and helps "manage" a wide range of other genes.
ERG: Another "gene manager" (transcription factor) that is known to target genes in both the immune system and the neurological system—the two key systems involved in MS.
L3MBTL3: A gene that builds an epigenetic "reader," which detects specific marks on histone proteins to help suppress other genes.
The team conducted a case-control study, comparing the DNA of 190 Iranian patients with relapsing-remitting MS (RR-MS) against 200 healthy individuals from the same population. They were looking for a simple answer: were any of these five variants more common in the patient group than in the control group?
The Results: Risk Dials and Protective Shields
It turns out, four of the five SNPs showed a significant link to MS. The findings paint a clear picture not of a single "on/off" switch, but of a series of "risk dials" and "protective shields."
The Risk Dials
Two genotypes were found to "turn up the dial" on MS risk:
SHMT1 (rs4925166): People with the GG genotype at this spot had a 1.9-fold higher chance of having MS. This was one of the strongest associations they found.
ERG (rs2836425): Having the TC genotype here was also associated with increased susceptibility, raising the odds by 1.89-fold.
The Protective Shields
Just as some variation increased risk, others seemed to offer a protective effect, "turning down the dial":
SHMT1 (rs4925166): In the exact same spot where "GG" was a risk, the TT genotype was protective, cutting the odds by more than half (OR 0.47).
ERG (rs2836425): Again, at the same location as the risk-raising "TC," the CC genotype was strongly protective (OR 0.50).
SHMT1 (rs1979277): At a different location in the same SHMT1 gene, the GG genotype was also found to be protective (OR 0.63).
MAZ (rs34286592): The GG genotype in this inflammation-response gene was linked to a protective effect as well (OR 0.61).
Interestingly, the fifth SNP, in the L3MBTL3 gene (the epigenetic "reader"), showed no association with MS at all in this particular population.
So, What Does This All Mean?
This study beautifully illustrates that our risk for complex diseases isn't about one "bad gene." It's about a combination of many small genetic factors that can gently tip the scales one way or the other.
But how?
A variation in SHMT1 might make the gene slightly less efficient. This could disrupt the delicate balance of DNA methylation (those "sticky notes"), causing important immune-regulating genes to be turned on when they should be off. It could also mess up the folate cycle, leading to a buildup of a neurotoxic amino acid called homocysteine, which has been linked to neurodegenerative problems.
A variation in ERG or MAZ—genes that act as managers for the immune and nervous systems—could mean they don't respond to inflammation signals correctly. They might overreact, or fail to "coordinate" the right response, contributing to the autoimmune attack seen in MS.
This research doesn't mean that having the "GG" genotype in SHMT1 causes MS. It just means it's one small piece of a much larger puzzle. It's a susceptibility factor. When combined with other genetic factors and environmental triggers, it might contribute to the "perfect storm" that allows MS to develop.
By identifying these subtle genetic links, especially in genes that control our epigenetics, scientists are building a much more detailed map of how MS begins. Each study like this one adds another crucial piece, bringing us one step closer to understanding the complete picture and, one day, finding new ways to intervene.
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:
Nazari Mehrabani, S.Z., Shushizadeh, M.H., Abazari, M.F. et al. Association of SHMT1, MAZ, ERG, and L3MBTL3 Gene Polymorphisms with Susceptibility to Multiple Sclerosis. Biochem Genet 57, 355–370 (2019). https://doi.org/10.1007/s10528-018-9894-1
