Genetic study points to NF-kappaB dysregulation in multiple sclerosis

Variation in genes controlling inhibitors of NF-kB strongly influences susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is known to be associated with both excess, chronic inflammation and with immune dysfunction. Since NF-kappaB is central to the control of inflammation, the researchers whose publication is summarized below investigated genetic variations associated with NF-kappaB in multiple sclerosis patients.

That is, rather than looking at the entire genome (all the genes in an individual) they only investigated those genes related to NF-kappaB. By focusing on and more closely examining NF-kappaB, more subtle differences could be investigated, especially the combination of slight differences between individuals with and without MS.  Specifically, they looked for mutations, polymorphisms and sequence variations (MPSV) in NF-kappaB related genes.

From the full text publication:

Generally, every 200-500 nucleotides will show random variation in humans. However, in the NF-kB gene sequence of approximately 7,000 nucleotides, they found only 2 such variations. (Based on the ‘normal’ rate of one every 200-500 nucleotides one would expect to find 14-35 such variations.)

The extent to which the exact sequence of nucleotides in the NF-kB genes are ‘conserved’ suggests the extreme importance of NF-kB, that some as yet mechanism is in place to protect such genes, and that NF-kB is, itself, not ‘broken’.

However, proper regulation of NF-kB (and hence proper regulation of inflammation) requires that the inhibitors of NF-kB also function properly.Various MPSV in the inhibitors of NF-kB could result in excess NF-kB activation, which would of course result in excess inflammation.

In looking at MPSV in the genes for the inhibitors of NF-kB, a number of polymorphisms (slightly different forms or sequences) were identified and found to be associated with and to increase the relative risk of MS.

Single polymorphisms were found to increase the risk of MS by up to 7.5x.

More intriguing, certain combinations of polymorphisms were found to increase the risk of MS by up to 12.8x.

“A major conclusion from this analysis includes that distinct combinations of alleles in the inhibitory part of the NF-kB cascade strongly influence disease susceptibility.”

Speculation

It is possible that these polymorphisms in genes encoding inhibitors of NF-kB result in a 12.8 fold increase in the risk for MS because they result in excess NF-kB activation (lack of inhibition) leading to inflammation, leading to myelin destruction and perhaps, ultimately, axonal damage.

It seems clear that MS results from a combination of many factors, genetic vulnerability being only one. However, to the extent the genetic vulnerability in MS results in over-expression (or over activation) of NF-kB, an effective treatment might be one which inhibits NF-kB. It seems possible, and reasonable, that natural NF-kB inhibitors might be useful in the treatment of MS.

The publication:

June, 2002

Inhibitors in the NF-kappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations.

Summary of the abstract

Multiple sclerosis is an autoimmune disease in which environmental as well as genetic factors contribute to the onset and progression of disease.

Several genes involved in the NF-kB cascade were analyzed. These genes are highly likely to play a role in multiple sclerosis because they are central to nearly all reactions in the immune system.

The genes in those with multiple sclerosis which code for NF-kB inhibitors were found to predispose to multiple sclerosis when present in certain variations, and especially combinations of variations, such combinations being identified in over 13% of those with multiple sclerosis.


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