Researchers in both fibromyalgia (FM) and chronic fatigue syndrome (ME/CFS) are doing deeper dives into the genetics of these illnesses than have ever been done before and they’re coming up with some surprises.
Travis Craddock of the Institute for Neuroimmune Medicine (INIM) at Nova Southeastern University (NSU) recently reported finding high rates of mutations in mucosal genes that produce the protective layers in our respiratory system, nose and eyes in ME/CFS (unpublished). Earlier, Liz Worthy took advantage of a Solve ME/CFS Initiative (SMCI) Ramsay Award to find evidence of genes associated with inborn errors of metabolism in ME/CFS.
Now, after a deep dive into the mitochondrial DNA of people in pain, a team of US and Canadian researchers has come up with a startling finding in FM.
A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia. Miranda Al van Tilburg 1 2 3, Marc Parisien 4, Richard G Boles 5, Gillian L Drury 4, Julian Smith-Voudouris 4, Vivek Verma 4, Samar Khoury 4, Anne-Julie Chabot-Doré 4, Andrea G Nackley 6 7, Shad B Smith 6, William E Whitehead 8, Denniz A Zolnoun 9, Gary D Slade 10 11 12, Inna Tchivileva 10, William Maixner 6, Luda Diatchenko 4 Pain. 2020 Jul 10. doi: 10.1097/j.pain.0000000000001996.
Chronic pain often runs in families, but most genetic pain studies have not found evidence of a strong genetic association. Those studies, though, have mostly focused on nuclear DNA – the DNA found in the nucleus of the cell. Our cells carry another kind of DNA, though – mitochondrial DNA that is contributed through the mother – and that’s the DNA this group tested.
We mostly associate the mitochondria with energy production – and they are the main energy producers in the body but they have other functions as well. Mitochondria are important for nervous system functioning and help to regulate the immune system. Mitochondrial issues also typically show up in tissues associated with high – and fluctuating – energy requirements such as the nerves and the muscles – two areas of concern in chronic pain.
This study was unusual in its large size and its attempt to assess the fully range of genetic polymorphisms (small changes in the genetic makeup) found in the 37 mitochondrial genes.
Each of the 609 participants were diagnosed with a “complex persistent pain condition” (CPCC): episodic migraine (n=263), irritable bowel syndrome (n=223), fibromyalgia (n=96) vulvar vestibulitis (n=100) and temporomandibular disorders (n=172 subjects). Plus, 237 healthy controls were included as well. Almost 70% were Caucasian and 23% were African American.
Eighty-five percent of the people with a CPCC were female. Interestingly, the highest rate of female dominance was in fibromyalgia (7.8 x’s more females.)
“Our results suggest that the m.2352T>C polymorphism has a strong clinical effect on the risk of fibromyalgia and possibly other chronic pain conditions.” the authors
They extracted the genomic DNA and then did deep sequencing and found that the FM patients stood out in another way: they and the vulvar vestibulitis patients were the only pain groups to have a significantly increased frequency of a specific genetic polymorphism; i.e. small change in one of the mtDNA genes.
(Vulvar vestibulitis refers to a condition characterized by severe pain in the vagina during intercourse, when using tampons or even when sitting on something like a bicycle seat. The pain can also be constant.)
In both groups, but more so in FM, an alteration in a single nucleotide (single nucleotide polymorphism (SNP) (m.2352T>C (rs28358579)) showed up with increased frequency in the MT-RNR2 ribosomal gene in women who a particular form of the gene called the c (minor) allele. An allele refers to a variant form of a gene and minor alleles refer to the second most common form of a gene in the population.
This small genetic alteration was also more evident, but to much lesser degree, in the other CPCC’s.
This gene, remarkably, had been unassessed in pain or other conditions, yet the evidence indicated that a small alteration in the gene was contributing to an increased risk for fibromyalgia and vulvar vestibulitis and perhaps other chronic pain conditions. (The polymorphism also increased the risk of a woman having more than one complex chronic pain condition.)
(One reason the polymorphism hasn’t been assessed much is that it’s found on an allele (the c (minor) allele) that is only very rarely found in Caucasian women and most genetic analyses have been done on Caucasian women. It is not currently assessed in 23andMe.)
Then they tested their finding in another pain cohort – the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) Study cohort – which contained 52 women with FM and over a 1,000 without it. The researchers must have been dancing a jig when they learned that their initial finding stood up: people with FM indeed had significantly higher rates of the polymorphism.
Their deep dive into the mtDNA appeared to have uncovered the first evidence of genetic weakness for coming down with a “complex persistent pain condition”.
The effect was strong; in fact, it appeared to be unusually strong. The authors reported:
“The replicated genetic effect size of the C allele on the disease risk (OR 5.1 and 4.3 in discovery and replication cohort, respectively) is impressive and has little precedence within the field of common diseases.”
An OR (odds ratio) of 5.1, if I have it right, means that having that particular SNP on that allele increased a woman’s odds of having fibromyalgia being present five-fold. That appears to be a huge number for a single gene polymorphism.
While having FM was significantly associated with having this polymorphism, the alternative c allele that the SNP was found in, was more much prominent in African American women and almost never found in women who identified themselves as Caucasian (1%). (Indeed, the odds ratio boomed in African American women to 7.6). Because the C allele had a stronger effect in a mixed population than in the African American population, it may have strongly affected other racial groups as well.
The SNP is located in the mitochondria’s 16S rRNA gene in the ribosome. Since this SNP has rarely been tested for, it hasn’t been associated with any other diseases or conditions. It’s not clear what it’s doing, but it may be hampering the ribosome’s ability to translate mRNA into proteins.
Mitochondrial functioning impacted
Next, they determined whether the polymorphism was actually impacting mitochondrial function. Obtaining ten cell lines from women with and without the polymorphism, they assessed the mitochondrial functioning of each one. Cells carrying the minor allele on which the SNP was found showed no difference in mitochondrial functioning (mitochondrial membrane potential) when put in glucose media (glycolysis), but when put in galactose media, their mitochondria membrane potential declined – indicating those cells were producing less ATP.
Mitochondrial Abnormalities in FM
It’s not clear how mitochondrial problems enhance pain, but several studies have implicated the mitochondria in FM. While this study illuminated a potential risk factor for African American women with FM, these other studies have broadly implicated the mitochondria in FM.
A gene expression study that highlighted reduced activity in a mitochondrial ribosomal gene suggested the mitochondria in FM may have taken a hit.
A recent FM animal model suggested the mitochondrial inhibition in the muscles and the spinal cord could play a large role in FM. Skin biopsies showed reduced mitochondrial activity and increased oxidative stress – two factors the authors suggested could be contributing to the high rate of small nerve fiber problems in FM.
A small family study suggested that a mutation in a mitochondrial gene – and the resulting increase in oxidative stress – could be playing a large role in some people with FM and suggested that future studies concentrate on people with family histories of the disease on the mother’s side.
Decreased ATP production in the muscles of FM patients has also been found. Reduced levels of coenzyme Q10 – a critical component in the electron transport chain in the mitochondria – have been found in FM and CoQ10 supplementation has been found beneficial in several studies.
The first really deep dive into the mitochondrial DNA in chronic pain uncovered a surprise – a rarely assessed genetic alteration (single nucleotide polymorphism – SNP) which was highly associated with fibromyalgia. The finding was potentially a big win for Black women with FM, many of whom may carry the form of the gene the polymorphism or SNP was found in. Caucasian women, on the other hand, rarely carry that form of the gene. When it was present, the SNP appeared to have an unusually strong effect and it will surely become the object of further study.
Further analysis suggested the SNP may be reducing ATP production in women with that form of the gene. While the SNP appeared to be mostly found in Black women with FM, the finding underscores the role the mitochondria may play in FM, and other studies have highlighted possible mitochondrial problems in the broad FM population and other chronic pain states. Tilburg’s earlier study of Caucasian women with IBS, for instance, suggested that a subset may have an mtDNA-related mitochondrial dysfunction.
In short, different mitochondrial problems could be contributing to the pain in FM in different ways. Mitochondrial issues could impair muscle functioning, producing oxidative stress, damaging the small nerve fibers, or by affecting nerve transmission elsewhere.
After years of work it’s time to attempt what we’ve never been able to do before – get Congress to force the NIH to double its funding for ME/CFS. Support the historic bill to increase research funding, add new ME/CFS research centers, require the development of a strategic plan, etc.. It will take less than 5 minutes.