“Irritable bowel syndrome (IBS) affects approximately 10.5% of the population (6.6% of men and 14.0% of women).[1]”

This is a continuation of what seem to have become a series of DNA Snps associated with CFS and conditions typically co-morbid.

• GI symptom severity was associated with ADRA1D rs1556832 (P = 0.010). [2015] –
  • rs1042717,  rs174697
  • not in 23AndMe

However this articles does include a table that may be helpful for understand what association means:

If the percentage in the Healthy Controls and the IBS Patients for one particular item are far enough apart, and after doing some mathematics, the researchers will conclude that is a positive or negative association of the SNP with a patient or a symptom. For example rs174697 for G/G we have 65.6% versus 78.8% (thus having it suggests IBS is more likely), while for A/G we have 28.1% versus 18.7% suggesting IBS is less likely (1.5x less likely – sometimes called the Odds Ratio or “OR” i.e. 28.1/18.7).

A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome [2015].

• [PMID 21636646] Association of TNFSF15 polymorphism with irritable bowel syndrome “The Crohn’s disease risk allele rs4263839 G in the TNFSF15 gene was significantly associated with an increased risk of both IBS (p=2.2×10(-5); OR 1.37) and more pronouncedly, IBS-C (p=8.7×10(-7); OR 1.79) in the entire sample.”
• [PMID 21304977] An investigation of genome-wide studies reported susceptibility loci for ulcerative colitis shows limited replication in north Indians.
• [PMID 25028192] Associations between TNFSF15 polymorphisms and susceptibility to ulcerative colitis and Crohn’s disease: A meta-analysis
• [PMID 25824902] A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome

Link: https://www.23andme.com/you/explorer/snp/?snp_name=rs4263839 

• The bad pair is “GG” (I have “AG”)

Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome [2014].

“Two SNPs associated independently in the exploratory and validation cohort: rs17837965-CDC42 with IBS-C (ORexploratory=1.59 (1.05 to 1.76); ORvalidation=1.76 (1.03 to 3.01)) and rs2349775-NXPH1 with IBS-D (ORexploratory=1.28 (1.06 to 1.56); ORvalidation=1.42 (1.08 to 1.88)).”

Only one SNP is available in 23AndMe, the one associated with diarrhoea.

Link: https://www.23andme.com/you/explorer/snp/?snp_name=rs2349775 (was previously associated with neuroticism )

• From the literature that I could find,  “CC” is likely the bad one.

There has been considerable interest in the DNA results for CFS and fibromyalgia is typically co-morbid, so I thought a browse through the research, especially for items that can be checked on 23AndMe.

As before, log on to 23andMe and then click the links below

Low COMT Enzyme higher pain in FM

COMT stands for  catechol-O-methyltransferase (COMT) gene.  Studies [2007] [2012] [2013]

Specific reactions catalyzed by COMT include:

• Dopamine → 3-Methoxytyramine
• DOPAC → HVA (homovanillic acid)
• Norepinephrine → Normetanephrine
• Epinephrine → Metanephrine
• Dihydroxyphenylethylene glycol (DOPEG) → Methoxyhydroxyphenylglycol (MOPEG)
• 3,4-Dihydroxymandelic acid (DOMA) → Vanillylmandelic acid (VMA)

Which may partially account for the relationship to pain. Interestingly “influences character traits and not only temperament” [2014] as well as “cognitive stability and cognitive flexibility” [2010]

Link: https://www.23andme.com/you/explorer/gene/?gene_name=COMT

The key SNPs are

• rs6269, Mine is AG
  • Type AA is associated with pain
• rs4633, Mine is CT
  • Type CC is associated with pain
• rs4818 — Not Found
  • Type CC is associated with pain
• rs4680 (Val158Met) — Mine is CT
  • AA is associated with pain
  • GG and AG are lower levels.

Severe Pain associated with the SCN9A Gene

“This association raises the possibility that some patients with severe FM may have a DRG sodium channelopathy.”[2012] found rs6754031 polymorphism to be most significant, unfortunately this is not included in the 23AndMe results for me.

Link: https://www.23andme.com/you/explorer/gene/?gene_name=SCN9A

Some SNP appear to be associated, but not at statistical significant levels (given the small sample) and less than half of the SNPs were listed in the 23andMe results.

• rs7607967 – AA (I’m AG)
• rs12994338  – CC (I’m CC)
• rs13017637 – CC (I’m TT)
• rs6746030 – AA – (I’m AG)

I have no FM pain and have only one of the above SNPs – which is what would be expected by randomness.

There are a number of of studies associating the Gene with pain sensitivity. For example:
” there was a statistically significant correlation between SNP rs6746030 and higher maximum NRS scores during the postoperative follow-up of non-PCA patients (P < 0.05). Furthermore, there was a significant association between the tag SNP rs4286289 and both increased postoperative maximum NRS scores (P < 0.05) and higher incidences of severe postoperativepain (P < 0.05) in non-PCA patients. Meanwhile, in PCA patients, rs4286289 exhibited the strongest association (P = 0.001) with increased requirements for postoperative analgesics, which indirectly strengthened the significant association between this SNP and higher postoperative pain.” [2016]

Predisposition to FM – T102C

T102C is the Rs6313 SNP

Link: https://www.23andme.com/you/explorer/snp/?snp_name=Rs6313

I am reported as AG on 23andMe. The CC variation is the one of concern.  SNPedia reports:

Bottom Line

Having the SNPs does not mean that you will or will not get FM. If you go into a FM state, your symptoms may be worst (and your FM state may actually be the same as someone with a lot less pain lacking these SNPs).

This information can be helpful to explain to a MD that your need for pain relief is higher because of your DNA. It could provide justification to the MD to prescribe a higher dosage based on evidence instead of tears.

As a speculation: There seem to be some evidence that mild and worst cases of FM/CFS is not strongly related to disease state, rather to DNA that is responding to the disease state.

Radical suggestion for treating pain!

One of my readers report that many pains disappeared in less than a month after aggressively trying to correct their microbiome. My model is that the symptoms are the results of the shift of chemicals being produced/released by the microbiome.  How the body responds to an increase or decrease of certain chemicals is influenced by the DNA. Symptoms like pain may be reduced or eliminated by shifting that chemical mixture — exactly how to  shift it is beyond current research literature.

Another DNA study was published in Oct, 2015 out of Norway which appears to be included in 23 and me results, but the key SNP is not there. It looked at the SLC6A4 gene. This gene is associated with OCD and anxiety  (which could present before CFS). An earlier 2015 study from Finland/India demonstrated that examining multiple SNPs at the same time was reasonable good in predicting people with CFS when some 1-200 SNPs were considered in combination. The study size was way to small to be used in practice.

Looking up on 23AndMe

After you logon to 23andMe, click the link below

https://www.23andme.com/you/explorer/gene/?gene_name=SLC6A4

And this should appear:

“Patients with the SS or SL_Ggenotype had a significantly lower number of steps per day and also a significantly higher FDI score than patients with the L_AL_G, SL_A or L_AL_A genotype when gender was taken into account as a covariate… we found that CFS patients with the 5-HTT SS or SL_G genotype had a more pronounced reduction in physical and psychosocial functioning than patients with the 5-HTT L_AL_G, SL_A or L_AL_A genotype. This suggests that patients with the 5-HTT SS or SL_G genotype have a less favorable 30 weeks outcome than patients with the 5-HTT L_AL_G, SL_A or L_AL_A genotype.”

FYI: The L_AL_G, SL_A or L_AL_A genotype are associated with medium to high serotonin production [2013].

” In accordance with previous studies of Caucasians or European Americans indicating a general 5-HTT SS or SL_G genotype frequency of about 25% [6,10], the same genotype frequency was 26% in the patients and 21% in the controls. Thus, the 5-HTT genotype cannot explain why some individuals develop CFS.”  – IMHO, it is associated with how the body responds to the microbiome shift seen in CFS.

Details

This link should take you directly to the SNP cited (SNP rs25531 A > G),

https://www.23andme.com/you/explorer/snp/?snp_name=rs25531

It is in the 23andme DNA(Thank you Livewello.com for catching the typo!) —

On Health Rising, it has been reported as “unreliable”   My personality type is a Polly-Anna, which would be consistent with the Genotype.

Recent related Studies

1. Gene-Environment Interaction in Youth Depression: Replication of the 5-HTTLPR Moderation in a Diverse Setting.Rocha TB, et al. Am J Psychiatry, 2015 Oct. PMID 26315979
2. [Association between the 5-HTTLPR Polymorphism of Serotonin Transporter Gene and EEG in Young and Postmenopausal Women].VolF NV, et al. Zh Vyssh Nerv Deiat Im I P Pavlova, 2015 May-Jun. PMID 26281230
3. Regional brain disorders of serotonin neurotransmission are associated with functional dyspepsia.Tominaga K, et al. Life Sci, 2015 Sep 15. PMID 26232557
4. Substrate and Inhibitor-Specific Conformational Changes in the Human Serotonin Transporter Revealed by Voltage-Clamp Fluorometry.Söderhielm PC, et al. Mol Pharmacol, 2015 Oct. PMID 26174773
5. Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.Frick A, et al. JAMA Psychiatry, 2015 Aug. PMID 26083190

Bottom Line

We cannot use 23andMe results to check our status — however, if prior to CFS, you were prone to OCD or Anxiety, then it is more probable that you have this gene variation.

For 25% of CFS patients, serotonin supplementation my result in improved results (especially with those with OCD or Anxiety prior to CFS).

A reader in Spain forwarded to me an article just published days ago, “Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome [2016]“. As expected, there was no outstanding results except for mtDNA (Mitochondrial DNA). mtDNA is inherited from the mother only, thus for some symptoms — a daughter’s symptoms may be the same as her mother in general.

The conclusions were

“We did not observe a significant association of mitochondrial DNA genome variation with either susceptibility or resistance to ME/CFS. We did not detect any significant difference in level of heteroplasmy between cases and controls. Using a cohort of 193 ME/CFS cases and 196 controls, at 5 % FDR we observed eight mtDNA SNPs to be associated with 16 symptom categories and three haplogroups associated with six symptom categories, suggesting that the mitochondrial genome of an individual with ME/CFS can affect the type and severity of particular symptoms.”

How to Check Yours!

I have reproduced the table 4 in the article and added a column showing my own SNPs below. For myself, the SNPs and symptoms were accurate! Below I explain how you can test your own DNA against this study.

Process

1. Log on to 23Andme.com
2. Click the link on the far right after logging on
3. A page will be rendered like the one shown below
4. 

Look at the Nucleotide position in the table and “Position” on this page. Then look to the right to see your value.  I have a value of “C” which is not the same as the symptomatic allele — hence it is likely not a symptom for me (and it is not).

Haplogroup and Symptoms

“All of the significant associations were with symptoms related to joint pain, bloating, or “feeling dead” after exercise. Haplogroup J showed a protective effect against all metrics of joint pain and individuals belonging to haplogroup U reported less severe bloating and had lower bloating distress scores compared to other haplogroups. On the other hand, ME/CFS individuals with haplogroup H tended to be more susceptible to “feeling dead” after exercise than other haplogroups.”

I am in the R1 haplogroup so there was no findings for me.

Bottom Line

The SNPs likely impacts how the body responds to shifts of the microbiome (effectively a chemical factory with many many chemicals) and are not a direct cause of the symptoms. The shifts are unique but with a lot of commonality — for example, some of these SNPs could be connected to D-Lactic Acidosis, a condition that could arise from many different bacteria in the microbiome.

Over the last 2 decades that I have been active in the Chronic Fatigue Syndrome, thyroid issues in patients with CFS has been a common chorus on many forums. I have not had thyroid issues (typically hypothyroidism or thyroiditis – too low levels) but a reader asked me to look at it — particularly from the microbiome aspects and hopefully with some probiotic interventions being possible. This is what I found:

Thyroid and CFS

There are over 60 pub med articles so it is not an incidental thing. Some high lights that I found are:

• ” Detailed analyses showed that thyroid disease (P<0.01) and gynecologic surgery (P<0.05) were significantly more common in FM.” [2015]
• Thyroid autoimmunity may represent a predisposition for the development of fibromyalgia? [2012] ” we observed that the presence of autoimmune thyroid disease worsens fibromyalgia (FM) symptoms … thus suggesting a hypothetical role of thyroid autoimmunity in FM pathogenesis.”
•  “Good responders [to B12 and folic acid] had used significantly more frequent injections (p<0.03) and higher doses of B12 (p<0.03) for a longer time (p<0.0005), higher daily amounts of oral folic acid (p<0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p<0.02), and no strong analgesics at all, [2015]
• “However, it is also known that iodine deficiency may give rise to clinical symptoms ofhypothyroidism without abnormality of thyroid hormone values…we will focus on the relationship between iodine deficiency and obesity, ” [2008]
• “The prevalence of thyroid dysfunction in women with suspected FM does not differ from that in the general population.” [2006]
  • “FM is often associated with other diseases that act as confounding and aggravating factors, such as rheumatoid arthritis (RA), spondyloarthritides (SpA), osteoarthritis (OA) and thyroid disease.” [2012]
  • ” This finding support thyroid autoimmunity may influence the development of FM, but the evidence which support that FM is related to autoimmune etiology is not clear,” [2012]

Obesity and Thyroid

This area has been heavily studied with over 1100 articles,

• ” The prevalence (percentage (95% confidence interval)) of thyroid autoimmunity was lower in the individuals with normal weight, 2.9% (2.0-4.2), than in those with overweight, 6.3% (3.9-9.9), and obesity, 5.6% (2.5-11.3) (p=0.02).” [2015]
• ” No differences in thyroid function were observed in both age groups. In the 6-8-year-old group, obese schoolchildren had higher iodine intake than normal-weight children (415.5 vs. 269.1 μg/day, p < 0.05), but no differences in salt intake. In contrast, in the 9-12-year-old group, obese schoolchildren had higher salt intake than normal-weight children (6.2 vs. 3.8 g/day, p < 0.05), but no differences in iodine intake.” [2015]
• Paradoxical relationship between body mass index and thyroid hormone levels; a study using Mendelian Randomization.[2015] “Our analysis shows that children with a genetically higher BMI had higher Free tri-iodothyronine (FT₃) but not FT₄ levels indicating higher BMI/fat mass has a causal role in increasing FT₃ levels.”
• Maternal hypothyroxinaemia in pregnancy is associated with obesity and adverse maternal metabolic parameters.[2016]
• Microbiome impact on metabolism and function of sex, thyroid, growth and parathyroid hormones. [2015]

Microbiome and Obesity

There are almost 500 articles dealing with probiotics and obesity. As expected, some probiotics increases weight gain and other reduces weight.

• “Experimental studies with gut microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic diseases.” [2016]
• ” L. plantarum FH185 was demonstrated that it has anti-obesity effect in the in vitro and in vivo test”[2015]
• “Lactobacillus reuteri GMNL-263 (Lr263) probiotics, which have been shown to reduce obesity and arteriosclerosis in vivo.” [2015]
• ” oral administration of L. rhamnosus and herbs resulted in a significant decrease in the body weight, epididymal fat mass, fasting blood glucose and serum insulin levels.” [2015]
• Anti-obesity effect of Lactobacillus gasseri SBT2055 accompanied by inhibition of pro-inflammatory gene expression in the visceral adipose tissue in diet-induced obese mice.[2014]

Or to cite a 2014 review of all of the literature “Analysis of the eligible articles pointed out that Lactobacillus gasseri SBT 2055, Lactobacillus rhamnosus ATCC 53103, and the combination of L. rhamnosus ATCC 53102 and Bifidobacterium lactis Bb12 may reduce adiposity, body weight, and weight gain. This suggests that these microbial strains can be applied in the treatment of obesity”  [2014]

Microbiome and Thyroid

• Link between hypothyroidism and small intestinal bacterial overgrowth. [2014] “It has been reported that SIBO may be present in more than half of patients with hypothyroidism.[1] Lauritano et al.[11] studied 90 subjects (hypothyroidism [n = 50] and control [n = 40]) and found that significantly higher numbers of patients (54%) with hypothyroidism have SIBO as demonstrated with positive glucose breath test compared with the control group (5%) (P < 0.001).[11] … A study with probiotic Bacillus clausii also showed promising results in SIBO. “
• DYSMICROBISM, INFLAMMATORY BOWEL DISEASE AND THYROIDITIS: ANALYSIS OF THE LITERATURE.[2015] -” The axis dysmicrobism-IBD-autoimmune reaction will be investigated as a possible etiopathogenic mechanism to Autoimmune Thyroiditis. If such is the case, then the employment of specific probiotic strains may represent a useful approach to moderate the immune system.”
• Does microbiota composition affect thyroid homeostasis? [2015]
• Gut microbe analysis between hyperthyroid and healthy individuals. [2014] “decrease of Bifidobacterium and Lactobacillus ((*) P < 0.05), and increase of Enterococcus ((*) P < 0.05) in the hyperthyroid group. “While this is the opposite of hypothyroidism, it does demonstrate that the microbiome plays a role.
• “Further studies are clearly needed to test the hypothesis that the gut commensal microflora represents an important environmental factor triggering Hashimoto’s thyroiditis.” [2012]

Thyroid and Vitamin D

Vitamin D is generally very low with FM and CFS, with symptom decreasing as the level increases. This raise the question whether there is an association of hypothyroidsim and vitamin D levels.

• Vitamin D and thyroid diseases. [2015] “, particularly levels below 12.5 ng/ml should be considered as an additional, but important risk factor for development of thyroid autoimmunity, both chronic autoimmune thyroiditis and Graves´ disease.”
• Low Serum Vitamin D Is Associated with Anti-Thyroid-Globulin Antibody in Female Individuals. [2015]
• The effect of vitamin D on thyroid autoimmunity in non-lactating women with postpartum thyroiditis [2016] ” The study’s results suggest that vitamin D supplementation may bring benefits”
  • “Baseline levels of 25-hydroxyvitamin D correlated with thyroid antibody titres, thyroid function”[2015]
  • “Our results also suggest that parathyroid hormone decreases quite linearly during vitamin D supplementation at any given 25-OHD level.”[2009]

Bottom Line

There is significant evidence that hypothyroidism is connected to the microbiome as well as obesity to the microbiome. There are no studies investigating if both are connected to the same shift. The association of a mother with hypothyroidism to a child with hypothyroidism appears to be more connected with the mother’s microbiome being passed along than DNA (which would be expected to connected to both parents).  The available literature suggests the following probiotics may improve these conditions (I’ve omitted the stains to simplify matter) – either by known anti-obesity effects OR by addressing SIBO.

• Lactobacillus gasseri,
• Lactobacillus rhamnosus,
• Lactobacillus reuteri
• Bifidobacterium lactis
• Bacillus clausii

Having a combination of these with other probiotics have the risk that the other probiotics may counter-act the benefits.

Additionally, Vitamin D is a clear benefit. If the microbiome is off, the absorption may be low so a rate of 10-15000 IU/day should be discussed with your medical professional.

Supplementing with Iodine is unclear. High levels appears to cause it “Does iodine excess lead to hypothyroidism? Evidence from a case-control study in India. [2015], so any supplementation should be done with care and testing.