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Genetic associations of fatigue and other symptom domains of the acute sickness

Discussion in 'Latest ME/CFS Research' started by Firestormm, Jan 15, 2012.

  1. Firestormm

    Firestormm Guest

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    Genetic associations of fatigue and other symptom domains of the acute sickness response to infection

    Brain Behav Immun. 2011 Dec 29. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/22227623


    Piraino B, Vollmer-Conna U, Lloyd AR.

    Source: Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Australia.

    Abstract

    The acute sickness response to infection is a conserved set of changes in physiology and behaviour, featuring fever, fatigue, musculo-skeletal pain, disturbed mood, and cognitive difficulties.

    The manifestations differ somewhat between individuals, including those infected with pathogens which do not have genetic variability - suggesting host determinants.

    Principal components analysis (PCA) was applied to acute phase, self-report symptom data from subjects in the Dubbo Infection Outcomes Study* (n=296) to empirically derive indices of fatigue, pain, neurocognitive difficulties, and mood disturbance, as well as overall illness severity.

    Associations were sought with functional single nucleotide polymorphisms (SNPs) in the cytokine genes, interleukin (IL)-6, tumour necrosis factor (TNF)-?, interferon (IFN)-?, and IL-10.

    The summed individual symptom indices correlated with overall severity and also with functional status. The relative contribution of individual symptom domains to the overall illness was stable over time within subjects, but varied between subjects with the same infection.

    The T allele of the IFN-? +874 T/A SNP was associated with increased fatigue (p=0.0003; OR: 3.3). The C allele of the IL-10 -592 C/A SNP exerted a protective effect on neurocognitive difficulties (p=0.017; OR: 0.52); while the A allele for the IL-10 -592 SNP was associated with increased mooddisturbance (p=0.044; OR: 1.83), as was the G allele of the IL-6 -174 G/C SNP (p=0.051; OR: 1.83).

    The acute sickness response has discrete symptom domains including fatigue, which have unique genetic associations. These data provide novel insights into the pathophysiology of fatigue states.'

    Copyright 2012. Published by Elsevier Inc.

    (*From Dr Shepherd MEA (https://www.facebook.com/pages/ME-Association/171411469583186) this morning:

    'The Dubbo Infection Outcomes Study was originally published in 2006 in conjunction with the CDC. The study was initiated as a Post-Infective Fatigue: A Model for Chronic Fatigue Syndrome according to the Federal Register. http://www.thefederalregister.com/d.p/2001-01-25-01-2269.

    The first study was published in the BMJ. <http://preview.ncbi.nlm.nih.gov/pubmed/16950834#> 2006
    Sep 16;333(7568):575. Epub 2006 Sep 1. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569956/?tool=pubmed

    The authors concluded: "A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome."

    Other papers published using this cohort can be found here: http://preview.ncbi.nlm.nih.gov/pubmed?term=Dubbo Infection Outcomes Study'

    He concludes 'This research links in with the study on fatigue markers in Sjogren's syndrome - a condition which has a number of symptomatic and pathological abnormalities in common with ME/CFS - that the MRC is funding in its new ME/CFS research portfolio.')
     
  2. currer

    currer Senior Member

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    There are three or four times as many people with ME now as with HIV in the UK.

    The dramatic rise in cases shows that ME cannot be explained away as a genetic disease. This must not be confused with inheriting a genetic predisposition to a certain pathogen or trigger..
     
  3. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    just searching IL6 and they seem to have IL6 inhibitors (tocilizumab) which are used in rheumatoid arthritis and other autoimmune conditions and help control inflammation. Its classed as an immune suppressive drug but only against IL6, so possibly wouldnt have supressive effects on other parts of the immune system. It looks like an attractive treatment option for me/cfs as we have this increased il6 which is said to be one of the main causes of sleep dysfunction in us which then compounds every other symptom we have.

    Immune abnormalities found in me/cfs people seem to keep coming up with autoimmune conditions in searchers i do. Im not saying we have an autoimmune illness yet but maybe autoimmune illnesses have an infectious cause too????? Interesting!

    http://en.wikipedia.org/wiki/Tocilizumab
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2621374/

    cheers!!!
     
    Firestormm likes this.
  4. Firestormm

    Firestormm Guest

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    This kind of amuses me Currer. On the one hand people say 'well the criteria are too broad so it includes too many people with different things' and on the other you are saying the rise in 'ME' is too great to justify this conclusion!

    Doesn't Dubbo look at post-infective states from a variety of 'triggers' and then narrows the cohort down as people recovered, leaving only those with the symptoms etc. after 6-12 months?

    As to this latest study, I cannot even begin to draw the conclusions you have until I read/get hold of the full paper.
     
  5. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    the above drug blocking il6 may not be a good thing for herpes viruses. The next link shows this with a person who had cmv http://wwwnc.cdc.gov/eid/article/17/4/10-1057_article.htm Does show how effective valcyte is on cmv even though used for a short time.

    there is a lot of overlapping systems and other things going on in the immune system, mmm.

    cheers!!!
     
  6. alex3619

    alex3619 Senior Member

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    This might help explain variations in symptoms between patients. It does not really address the whole PVFS vs ME question, nor the one disease or many or a spectrum issue. For that we need better biomarkers - we need to be able to pin down what PVFS and ME are at a molecular level, and use this to subgroup patients. We are not there yet. Bye, Alex
     
  7. markmc20001

    markmc20001 Guest

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    Viruses are used in gene therapy research. Maybe some of us(or our parents) got some unwanted gene therapy along the way?

     
  8. SOC

    SOC

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    Why not?

    What if 10-25% of people have the genetic issue and the triggering pathogen(s) is increasing in prevalence in the western world over the past, say, 75 years? Not everyone exposed will have the genetic defect, nor will everyone with the genetic defect be exposed. If the pathogen runs rampant in a close environment such as a hospital, a symphony, or a school where everyone is exposed, a substantial number of people will develop ME. If the pathogen is spreading slowly in a broader environment, only a few of the genetically predisposed will be exposed and there will only be sporadic cases.

    I'm not saying this IS the case, just that it's not an impossible scenario.
     
  9. alex3619

    alex3619 Senior Member

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    Hi SOC, I agree. I have discussed this before in the context of epidemic growth curves. The growth curve for ME could look very scary, but a requirement for genetic predisposition will see it spread fast and then slow, not keep rising. I raised it in relation to the question: why don't we have epidemics any more? A possible answer was that we were approaching the limit of genetic susceptibility, not there yet but getting closer. I don't know which version of events is right, without better evidence it is hard to say.

    On the other hand it could be be that CFS definitions have stuffed up the reporting of epidemics. Did not 8% of SARS patients come down with something resembling ME? Do we count them or not?

    Bye, Alex
     
  10. Firestormm

    Firestormm Guest

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    Note sure how one can talk about growth in populations etc. when identification, classification and epidemiological studies are so woefully inadequate.

    From one perspective there isn't much (if anything) to distinguish PVFS from CFS from ME not when you look e.g. at symptomology. Indeed many of us I suspect reached our ME diagnosis from PVFS - well I did in part.

    Anyway, will try and get the full paper and have a read. Am hoping to read the Dubbo study in full later if I can.
     
  11. alex3619

    alex3619 Senior Member

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    http://www.name-us.org/ResearchPage...cArticles/Underhill2006FamilyPrevalenceAb.pdf

    This paper from the Journal of CFS shows that, at least in this study, children have a 5% chance of becoming ill if their parents have it, and spouses/partners 3%. Its not just genetics. There is some kind of lifestyle, environmental or transmissable factor involved. Near relatives had an 0.8% chance, and siblings over a 1% chance, which might indicate that genetics do play a part.

    Cheney used to plot CFS growth curves. They were scary. The problem is the data is too difficult to obtain and has too much noise. Recent claims of prevalence rates over 1% either represent an error, or a severe climb in prevalence. The data is so poor I can't tell which might be right - I suspect error due to loose definitions.

    Bye, Alex
     
  12. Mark

    Mark Acting CEO

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    I think this is exactly what Currer was saying - that It can't just be explained away as a purely genetic disease; even if genetic factors are necessary, that doesn't rule out a novel pathogen. SOC and Alex have expanded on Currer's point, not contradicted it.

    So I think we are all in agreement on this point; this commonly causes confusion, a lot of people I speak to tend to want to think in boxes and decide it's one thing or another, but I agree that it does look like there is genetic susceptibility to environmental factors that have increased in prevalence, and those environmental factors could very well include a novel pathogen or pathogens of course.
     
  13. SOC

    SOC

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    Ah, thank you for that clarification, Mark. I guess my cognitive dysfunction is still giving me trouble. :oops:



    As for epidemics, I wonder if there are still epidemics but they are not recognized as such because of either poor definitions or lack of knowledge/recognition.

    For example, within our small homeschool group (50 families), there are 5 diagnosed cases of "CFS", 3 or 4 chronic Lyme, 2-4 fibromyalgia, and 1 or 2 atypical MS, many as mother-child sets and all including children about the same age (now 19-24). Illness started showing up about 7 years ago when the kids were mostly in the same secondary level activities (ages 12-17).

    These are just the cases I know, but it suggests to me the possible passage of a pathogen through this fairly high-contact group and only affecting genetically susceptible individuals.

    However, because we have a variety of diagnoses (our doctors' best guesses?), we are not recognized as an epidemic group. Or, perhaps genetic differences have us reacting differently, but with similarities, to the pathogen.

    My current best guess (subject to change at any moment) for a possible pathogen is HHV-6A. It is about to be reclassified as a virus distinct from HHV-6B, which is extremely common in the western world. Very little is known about HHV-6A other than that it is very neurotropic, much more so than HHV-6B, and is probably associated with MS. Most of what is known about HHV-6 applies to either HHV-6B or an unknown combination of A and B which just clouds the issue.
     
  14. alex3619

    alex3619 Senior Member

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    Medical Reporting Burnout Syndrome, MRBS: too much for too long, the docs got sick of doing it because its everywhere now? ;)
     
  15. Purple

    Purple Bundle of purpliness

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    To illustrate the problems with recording clusters of ME, consider the following hypothetical scenario:

    A large office in a large company, in a large city. Due to the size of the city and the company, the employees homes are scattered around (e.g. some are 1.5 hours north of the office, some 1 hour east, some nearby etc.) and so are their doctors.

    An unusual pathogen enters into this situation. This bug spreads through the office: within 8 months, quarter of the office had the flu from hell; they spend up to 4 weeks in bed, some so dizzy they feel faint, and when they come back to work, some are pale and a little weaker for a few weeks afterwards. Some have a few flu-like illnesses in a row. Many get this bug: from support staff to directors. But because the individual peoples flu illnesses are spread over the autumn, winter and into spring and the different departments dont communicate with each other very much, nothing out of the ordinary is noticed: after all, you expect people to catch the flu this time of the year anyway, its normal to have two or three of people off sick at the same time in a department...

    Majority recover normally, however, some dont. Such as the following hypothetical patients who all get sick with ME or CFS or PVFS or fibromyalgia at the same time:

    1. Patient A is a support staff contractor who after a short flu descends into moderate ME over several months which means she has to quit working when the contract comes to an end. GPs verdict: CFS. Nobody at the company was aware she was sick when she left. 7 years on, she is bedbound and isolated.

    2. Patient B is a short term contractor. He gets this flu just as his contract ends. He gets over it normally. He moves to another country for another job soon after.

    3. Patient C is Patient Bs wife. She gets the flu which leaves her with lots of pain afterwards. It gets worse over time and more symptoms appear. After years of investigations, she ends up with the diagnosis of fibromyalgia from a rheumatologist in another country. She is also a severe ME sufferer but this is not taken into account as only fibromyalgia is recognised and treated in that country.

    4. Patient D sat next to Patient A every day but they didnt talk much to each other due to work load. Patient D also had the flu for 4 weeks and symptoms included severe dizziness. Mild dizziness persist for another 1.5 years, then it comes and goes for another 5 years or so. No diagnosis is given as Patient D decided not to go back to the doctor after the initial basic tests came back clear.

    5. Patient E is the husband of Patient D. He was off work for 4 months with the flu, he still has some symptoms, mainly pain, fatigue, digestive and sleep problems, which he keeps to himself; 7 years on he works part time. Working part time is common in his field so it is generally assumed to be a life style choice by those around him. Initial diagnosis of Post Viral Fatigue Syndrome from GP, he no longer sees the doctor about it.

    6. Patient F is in a senior position in the company and has 3 children to support through college. He is aware he has not been healthy since the flu but he is the breadwinner in the family. He makes practical arrangements to be able to carry on earning as long as possible. After 7 years (when the last child finishes college), he takes the early retirement. By now, there are additional age-related diagnoses: diabetes, high blood pressure. He also has a diagnosis of ME from a private specialist but does not make this public. He crashes into bed as soon as he stops working.

    7. Patient G is the office manager. He suffers with symptoms of fatigue, painful joints and muscles, concentration issues, heart palpitations and vertigo attacks since the flu. After months of investigations and due to his stressful position at work, he receives the diagnosis of stress which he accepts without questioning. He is a highly-driven individual who carries on working full time in his sedentary job, spends his holidays recuperating and has no life outside of work.

    8. Patient H suffers from an autoimmune disease, symptoms of which include fatigue, pain and balance problems, and takes immuno-suppressive medication for it on a regular basis which can also cause some of the symptoms. When the symptoms increase and change after the flu, this is attributed to the original illness and not ME.

    Etc.

    Fast forward 7 years from the original flu from hell. So: in this hypothetical situation, (most of) these patients would know nothing about each others illnesses despite being in close proximity at the time, and they have little chance of finding out about each other later. There is little chance of anyone connecting these cases of differently-labelled illnesses into a cluster

    (Sorry this is long and I hope it is not off-topic.)
     
  16. SOC

    SOC

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    Yeah! That's it! :D
     
  17. oceanblue

    oceanblue Guest

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    Commentary

    I've now read the full paper; I'm not sure how relevant it is to CFS but here are some comments anyway.

    Background
    This work comes from the landmark "Dubbo Infectious Outcome Study" (aka DIOS, or just Dubbo) that studied the progression of nearly 300 people with one of 3 different illnesses that often lead to CFS, or PIFS (post-infectious fatigue syndrome). What makes the study so interesting, from my perspective, is that it found the strongest predictor of developing PIFS was the severity of the initial infection. This contrasts with findings from other studies of glandular fever (one of the 3 illnesses Dubbo covers) that psychological factors are important in predicting CFS/PIFS.

    A key paper from this study, published in 2008, found that cytokine polymorphisms were linked with the severity of the initial illness, specifially SNP polymorphisms of Interferon-gamma (IFN-g) and Interleukin 10 (IL10). This new paper looks at links between cytokine polymorphisms and specific aspects of illness severity, eg fatigue and pain.

    The study itself
    The starting point is that most of the symptomes of sickness are produced by the patient not the pathogen: "The acute sickness response to infection is a conserved set of changes in physiology and behaviour, featuring fever, fatigue, musculo-skeletal pain, disturbed mood, and cognitive difficulties". The paper then examines how the balance of these symptoms varies between patients, and it's link to cytokine polymorphims.

    The authors took self-report data from questionnaires covering 51 possible symptoms (some overlapping between questionnaires) and analysed them with a technique call Principal Component Analysis, which basically finds clusters of symptoms. 4 overall types (or domains) of symptoms emerged from this analysis: Fatigue, Pain, Neurocognitive difficulties (eg concentration) and Mood Disturbance.

    They then applied these symptom domains to give a score for each patients for each symptom domain.

    The first thing they found was that different patients had different patterns of symptoms; some had more pain, others more fatigiue etc. Crucially, it didn't matter which infection they had (EBV, Ross River Virus or Q Fever); patients had a range of different symptom patterns is all 3 infections. The one constant was that for each patient, the overall symptom pattern (eg lots of neurocognitive problems, little pain) remained fairly constant throughout the illness (where the illness was prolonged).

    Next, they looked to see if the types of symptoms each patient had was linked to the version of cytokine gene they carried, since cytokines have been heavily implicated in the acute illess response. And lo! It was correlated, at least in some cases:

    Interferon-gamma (pro-inflammatory) increased fatigue:
    The 'putative high cytokine producing T allele of the IFN-c +874 T/A SNP was the best predictor of severe fatigue [p < 0.001; OR (Odds Ratio): 3.6 (95% confidence interval (CI): 1.87.2]'.

    IL-10 (anti-inflammatory) was protective for neurocognitive problems:
    "subjects homozygous for the high producing C allele of the IL-10 -592 C/A SNP were significantly less likely to experience neurocognitive difficulties [p = 0.005; OR: 0.44 (95% CI: 0.250.78]". This makes sense as IL-10 is anti-inflammatory so should dampen down the host response to infection, reducing symptoms.

    IL-10 (the other allele) and IL-6 combined to increase mood disturbance:
    "The putative high producing G allele of the IL-6 -174 G/C SNP was associated with greater mood disturbance [p = 0.027; OR: 2.2 (95% CI: 1.14.4], while the IL-10 -592 C allele exerted a protective effect [p = 0.014; OR: 0.44 (95% CI: 0.230.85]."

    "Moreover, those individuals who had both the G allele of the IL-6 -174 and an A allele for IL-10 -592 (i.e., a high IL-6 low IL-10 combination) had a greatly increased risk for mood disturbance [p = 0.004; OR: 5.3 (95% CI: 1.716.2]."

    Given the number of comparisons made between polymorphisms and symptom, I think it might have been appropriate to adjust for multiple comparisons by lowering the p threshold for significance, so p=0.027 for IL-6 might be a little iffy; but then the combination of IL-6 with IL-10 looks pretty convincing.

    Nothing (apart from having Ross River Virus) correlated with pain.

    Gender was important too:
    Women 'were more likely grouped in the high fatigue extreme [p = 0.01; OR: 2.3 (95% CI: 1.24.6]';
    Female sex was the strongest predictor for neurocognitive difficulties during acute illness [p = 0.001; OR: 2.9 (95% CI: 1.65.4] and for severe mood disturbance during acute infection [p < 0.001; OR: 3.9 (95% CI: 1.97.9].

    Take out
    The biggest predictor of how your body reacts to an infection is not the specific infection (at least for the 3 infections studied here) but your sex and the versions of cytokine genes you have. The authors don't say how much of the total variance (in terms of overall illness severity, and severity of symptom type) is accounted for by sex and cytokine polymorphisms, so we don't know if it's most of the variance of just a small part.

    Note that this particular paper did not look at the association between symptom type and the risk of developing CFS/PIFS, though the authors do conclude by saying:
     
  18. Firestormm

    Firestormm Guest

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    Well done Ocean! I haven't even read the darn thing through yet [sigh]. I will get round to it.
     

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