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Autism SNP's, Interferon, & Chemokines

LaurieL

Senior Member
Messages
447
Location
Midwest
I would like to start this new thread so as not to completely hijack KDay's thread on geneticgenie. I also think Autism is absolutely related to CFS/ME, as some of the principles and treatments associated with ASD have worked so very well for me personally.

Kday posted testing SNP's relating to Autism in which I investigated my own results at 23andme. Natasha posted related Interferon and chemokines associated with those with ASD. My investigations were intersting in that my results correlated with the information the both of them presented. I have copied some of their posts here to start the thread. Thank you both for this avenue.

This is really exciting... A genetic risk test based on 65 SNPs is out for Autism and is currently being tested by the Cleveland Clinic.

It has 65 SNPs, and 23andMe as every single one of them.

How this will help ME/CFS? I have no clue. I'd be very curious if we have high "Autistic" scores as I feel Autism and CFS may have a very similar genetic setup. And if this turns out not to be true, it can help the Autism community.

http://www.arisktest.com/28-understanding-the-report.htm

Full list of SNPs

http://www.integragen.fr/upload/Documents/ARISk Test SNPs.pdf

edit: It turns out their methods (using SNPs) for assessing autism risk are patented, so I don't know how much I could do with it. I am kind of wandering in the gray zone though so I don't really know how patent laws would apply to me.

There were 36 total SNP's for females. My results include:

(14) Dominant = 8(+/+), 3(+/-)
(11) Recessive= 4(+/+), 4(+/-)
(11) Additive= 7(+/+), 2(+/-)

Total (+/+) = 19
Total (+/-) = 10
Total (-/-) = 6
NoCall= 1

kday said:
I suspected that ME/CFS would score high on that test because it is my belief that Autism is the same illness. If anyone else wants to post their results, I've automated it and I can send you the link.​
Remember that on some SNPs you have to change the risk allele letter.​

Hi kday, have you seen this on autism risk genes


The five immunological and inflammation gene sets (iCNV-5) again ranked topmost. ...​
... there is a loss of genomic copies in the interferon alphas (IFNA10, IFNA14, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA8, IFNA17) and gain of copies in the “C-C” motif chemokine ligands (CCL1, CCL11, CCL13, CCL2, CCL7, CCL8) as summarized in Table 1. Several of these chemokines have been found to be overexpressed in inflammatory diseases ... The loss of interferon alpha copies, usually implicated in the response to viral infection and another component of innate immunity, could also account for a dysregulated, secondary or compensatory response of interferons and chemokines. Several of these messengers “…are produced by neurons and glia in the adult brain, and that they can acutely influence synaptic transmission.​
... The above could be suggestive of a link between in utero infections and brain development in the child. Thus, the genetic background by itself would not be enough via this view to cause a deranged developmental process which would rather only occur in the presence of relevant infections. Interferons are important in the control of viral infections via the induced expression of interferon-stimulated genes [40]. The loss of copy number in the interferon genes suggests a possible reduced expression of such genes when stimulated. Thus, a viral infection would last longer under such a genetic background. Viral infections also lead to the expression of various chemokines in the CNS [41]. Further, chemokines are also involved in brain development [27],[41]. There would therefore be a longer generation of chemokines and other cytokines that could interfere with normal brain development. Further, gain in copy number in chemokines may lead to higher levels of these chemokines and would thus exacerbate the derangement in brain development. ....​
do these findings match yours and and how do they compare to CFS/ME findings ?
...Natasha

I went to 23andme, in the Interferon genes or IFNA, I had quite a few results in which NO GENE FOUND was recorded. Whether that is due to deletion as stated in Natasha's quote, or whether 23andme did not test for it, I do not know. None the less, it is interesting for a follow up. The interferon genes are quite specific in 23andme, and only one result is given for each. I do not believe there is a risk allele associated with the INFA and correlating number. But for the chemokines, there are several SNP's listed and of which I am missing information on risk alleles to make an assessment of the SNP's listed.

Natasha, anyone, do you have the risk alleles associated with these SNP's?

There are ten (10) IFNA's listed. Out of those 10, I only have 3. 7 out of the 10 came back as NO GENE FOUND.

Here is a list of what was mentioned in Natasha's post and source quoted. I have included the SNP rs#'s except for those genes that were not found in my DNA profile for IFNA.

NGF= NO GENE FOUND

IFNA10 rs 12555631
IFNA2 rs10120977
IFNA14 NGF
IFNA22 NGF
IFNA4 NGF
IFNA5 NGF
IFNA6 NGF
IFNA7 NGF
IFNA8 rs16938396
IFNA17 NGF

As an aside, this would explain why my projected response to interferon treatment should I contract hepatitis would be compromised as stated in my 23andme profile.

The following is where I need risk alleles... (or is the "gain of copies in the c-c motif they refer to?)

CCL1 rs3136682
CCL1 rs2282692
CCL1 rs159271
CCL1 rs3138032

CCL11 rs1129844
CCL11 rs1860184
CCL11 rs3815341
CCL11 rs4795898
CCL11 rs1019109

CCL13 rs3136677
CCL13 rs159313

CCL2 rs2857657
CCL2 rs4586
CCL2 rs13900

CCL17 rs3091237
CCL17 rs3091321

CCL8 rs3138036
CCL8 rs1133763

Again, thank you for all of this.

LaurieL
 

LaurieL

Senior Member
Messages
447
Location
Midwest
An example of intestinal dysbiosis and the ability of bacteria to suppress interferon. With interferon interference, white blood cells would be low even in the presence of infection. Cytokines activated and protracted.

http://www.ncbi.nlm.nih.gov/pubmed/12525001

Zh Mikrobiol Epidemiol Immunobiol. 2002 Sep-Oct;(5):48-53.
[Specific biological features of opportunistic bacteria determining dysbacteriosis in the composition of the large intestine normal microflora].

[Article in Russian]
Levanova LA, Aleshkin VA, Vorob'ev AA, Afanas'ev SS, Surikova EV, Rubal'skiĭ OV, Aleshkin AV.
Source

State Medical Institute, Kemerovo, Gabrichevsky Research Institute of Epidemiology and Microbiology, Moscow, Russia.

Abstract

Dysbiotic manifestations in the gastrointestinal tract are widely spread. They are characterized by a prolonged, persistent course with the tendency to transition to the chronic form and poorly respond to corrective treatment. The occurrence of high concentrations is 70% for Klebsiella oxytoca, while for K. pneumoniae--within the limit of 30%. The most topical problem is colonization of the intestinal mucosa in children aged up to 1 year by Klebsiella, the seeded bacteria retaining their capacity for growth for up to 2-3 years despite the use of probiotics. As shown in this study, the occurrence of Klebsiella and the level of the antilysozyme and "antiinterferon" activity of these bacteria, their resistance to antimicrobial preparations increase, correlating with the level of dysbiotic disturbances.

PMID: 12525001 [PubMed - indexed for MEDLINE]
 

Research 1st

Severe ME, POTS & MCAS.
Messages
768
Hi Laurie L

Do you know if people with ME or CFS report increased rates of Autism in their blood related families? I wonder if any research or discussions have been had on this matter?
I'd love to know.

Certainly when I read people interested in the biology of Autism I notice a similar inflammatory profile associated to what is called CFS. (Chemokines and TH1/TH2 profile).

Looking at the most recent ideas on Autism, scientists now propose that Autism is not just a 'genetic' problem but more of an environmental issue I think. E.g. what we come into contact with in society.

What seems to be preventing this information getting out is the apparent ease of which children are diagnosed as being Autistic not because they have developmental Autism and retardation (Autism is within the category of mental retardation, e.g. delayed developmental learning) but because they have behavioural problems, ADHD and are a little 'Aspie' in nature.

So Autism is being diluted by psychiatrists meaning its getting hard to propose a neuroimmune disease model for Autism.

I like this website, have you seen it?
https://www.stopcallingitautism.org/


Their front page says: ''Evidence indicates that children with autism suffer from an ongoing neuroinflammatory process in different regions of the brain involving microglial activation.
Microglial activation result in a loss of connections between the neurons reducing their function and leading to what is known as autism.''

I thought that was interesting as 'CFS' (ME) also can involve micro-glial activation if one measures blood chemokines and/or is fortunate to have a PET scan.

Thank you.
 

LaurieL

Senior Member
Messages
447
Location
Midwest
Hello R1,

Do you know if people with ME or CFS report increased rates of Autism in their blood related families? I wonder if any research or discussions have been had on this matter?
I'd love to know.

There have been several "mentions" on this forum, and some references, in which interested me enough to follow up on, plug in my data, and see how it compared. With my own experiences, these were some of the most effective treatments I received, and these were derived from Autism treatments. I was working from both communities (Autism and CFS/ME) with the mind set that yes, they have very similar immunological profiles and resulting cascades there in. I was also asked to take a research study survey by 23andme in which then piqued my interest further. (The fact that they would have this survey, would lend a certain air, don't you think? I also have the classical profile for CFS.

On another note, as far as my family. Nobody officially diagnosed to my knowledge. We did suspect my brother to have Aspberger's. And now that I think about it, I think my mother would have been a good candidate. As far as myself growing up, it was never suggested, or presented, or mentioned. Not one thing about my mother either. But there is a certain presentation, and she fits it. It explains a lot to me. (There is a 23 year difference between the brother I reference and myself). I remember the doc's suggesting that perhaps it was a result of the age in which she had him, 43. But now,...I don't think so.

Certainly when I read people interested in the biology of Autism I notice a similar inflammatory profile associated to what is called CFS. (Chemokines and TH1/TH2 profile).

I agree on the cytokines, but I have seen both Th1 dominance, and Th2 dominance, and swings back and forth as well.

Looking at the most recent ideas on Autism, scientists now propose that Autism is not just a 'genetic' problem but more of an environmental issue I think. E.g. what we come into contact with in society.

I cannot agree with you on this one. I believe they stick this label on this type of research, for two reasons. 1) To support a psychological diagnosis (because if it is strictly environmental, then the prospect of finding those elements are impossible, thus lack of funding), and 2) to account for the huge upswing in the occurrence of Autism. Yes, the pool is diluted with other conditions, such as the ADHD, etc; but if they really did a comparison of the genetic mutations, I believe that dilution would cease.

What seems to be preventing this information getting out is the apparent ease of which children are diagnosed as being Autistic not because they have developmental Autism and retardation (Autism is within the category of mental retardation, e.g. delayed developmental learning) but because they have behavioural problems, ADHD and are a little 'Aspie' in nature.

Mental retardation has differing degrees and affects. The same with Autism, in that Aspberger's and ADHD have similar profiles. What they don't know is whether it is due to the differences/similarities in environmental exposure and/or genetic mutations, or both. Hence the investigations into the environmental aspect. Of which I believe will not be the sole determining factor of the occurence, much less the spike in diagnoses. And the spike is occurring around the world. I think it is a great disservice to label this spike as correlating with an increase in environmental exposures. If genetics didn't have anything to do with it, then every blood line would succumb to one of these. There is no way environment can explain the spike,.....well, there might be one thing, but onward.

So Autism is being diluted by psychiatrists meaning its getting hard to propose a neuroimmune disease model for Autism.

Every chronic disease out there is being labeled as psychiatric. There's a lot of pills to be given out, and a lot of money to be had.

I like this website, have you seen it?
https://www.stopcallingitautism.org/


Their front page says: ''Evidence indicates that children with autism suffer from an ongoing neuroinflammatory process in different regions of the brain involving microglial activation.
Microglial activation result in a loss of connections between the neurons reducing their function and leading to what is known as autism.''

I thought that was interesting as 'CFS' (ME) also can involve micro-glial activation if one measures blood chemokines and/or is fortunate to have a PET scan.

No, I haven't but I will go check it out. And yes, I find that interesting as well.

Nice to meet you, and thank you. I appreciate the response. It saved me from talking to myself on this thread.

LaurieL
 

LaurieL

Senior Member
Messages
447
Location
Midwest
I like this website, have you seen it?
https://www.stopcallingitautism.org/

Interesting, but it doesn't state why the microglial activation takes place. Being a part of the immune system response, what sets it off? You know, I have seen many times, that the connections to Autism, ASD's, FMD, Alzhiemers, and others like diabetes and Thyroid problems, are G-proteins and GAG's. I propose that the G-proteins and GAGS could go one step further in saying that these all have acquired glycosylation abnormalities of proteins. Acquired glycoprotein disorder, not CGD.

LaurieL
 

LaurieL

Senior Member
Messages
447
Location
Midwest
I found this interesting...

http://journals.cambridge.org/abstract_S1740925X12000142



Evidence of microglial activation in autism and its possible role in brain underconnectivity

Juan I. Rodrigueza1 and Janet K. Kerna1a2a3 c1

........Naik et al. (2011) examined NF-kB in peripheral blood
samples of 67 children with autism and 29 control children
using electrophoretic mobility shift assay. They stated that
there was a significant increase in NF-kB DNA binding
activity in peripheral blood samples of children with autism
and when the fold increase of NF-kB in cases (n ¼ 67) was
compared with that of controls (n ¼ 29), there was a significant
difference (3.14 versus 1.40, respectively; P , 0.02).
They concluded that autism may arise, at least in part, from
an NF-kB pathway gone awry.


Evidence suggests that the equivalent of a vicious cycle can
occur where microglia produce oxidative products and then
increased intracellular reactive oxygen species (ROS), in
turn, activates a redox-sensitive NF-kB to provoke excessive
neuroinflammation. According to Nakanishi et al. (2011),
this can result in memory deficits and prolonged behavioral
consequences...
 

LaurieL

Senior Member
Messages
447
Location
Midwest
Here is some of the reasoning in why I am of the opinion that limiting the neuroinflammation to environmental causes or pyschological disease cannot be narrowed such that one generality can account for.

NFKappaB

Its triggers are known to be either environmental, endogenous, or infectious. These triggers include, "stress", Radiation, Oxidative Stress, Injury, Bacterial LPS, Viral Infections, Leaky gut and bacterial translocation, Food allergies, Environmental allergies, Diets high in macronutrients(Sugars, Lipids, and Proteins), Nutrient deficiencies, and Arachnidonic Acid Metabolites, to name a few...

These lead to activation of NFKappaB.

Which then leads to genetic expression for genes coding for pro-inflammatory and anti-apoptic cytokines.

Which then leads to cytokine production, the production of adhesion molecules, and pro-inflammatory enzymes.

The following seven listed occur along this pathway. Those seven being the production or induction of:

1) IL-6 = CRP
2) COX2 = Prostaglandins (PGE2) and/or Thromboxanes
3) IL-1 = Collagenase/MMP
4) Lipooxygenase = Luekotrines
5) iNOS = NO
6) TNF-a
7) Adhesion molecules

And of which all lead to negative feedback loops, which are incredibly hard to break, once they start. Which is why a cytokine storm is so incredibly hard to control and the treatment is palliative and supportive.

These negative feedback loops then lead to more IL-1 and PGE2, ROS and oxidative stress, and more TNF-a and CRP. Viscious little cycle, and genetics absolutely play a part. As the triggers are highly variable and modifiable, and the genetic expression from one individual to another is as well.

All of this then leads to pain, inflammation, cardiovascular disease, neurodegeneration, Insulin resistence, Autoimmune disease, Rheumatic disease, and yes.....cancer too.

So compared to the controls considered normal, and those with Autism with higher then normal levels of microglial activation, and then those of us with CFS/ME, what predisposition exists, and do they differ with the trigger? How come I have been functional albeit I have had trouble with infections my entire life, but functional up until a certain point, and then I was knocked flat.
 

LaurieL

Senior Member
Messages
447
Location
Midwest
I have always had one question in my mind. Were the mutations that we see now, in our results, were they there at birth as well? What about those kids with early diagnostic Autism?
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
Here is some of the reasoning in why I am of the opinion that limiting the neuroinflammation to environmental causes or pyschological disease cannot be narrowed such that one generality can account for.

NFKappaB

Its triggers are known to be either environmental, endogenous, or infectious. These triggers include, "stress", Radiation, Oxidative Stress, Injury, Bacterial LPS, Viral Infections, Leaky gut and bacterial translocation, Food allergies, Environmental allergies, Diets high in macronutrients(Sugars, Lipids, and Proteins), Nutrient deficiencies, and Arachnidonic Acid Metabolites, to name a few...

These lead to activation of NFKappaB.

Which then leads to genetic expression for genes coding for pro-inflammatory and anti-apoptic cytokines.

Which then leads to cytokine production, the production of adhesion molecules, and pro-inflammatory enzymes.

The following seven listed occur along this pathway. Those seven being the production or induction of:

1) IL-6 = CRP
2) COX2 = Prostaglandins (PGE2) and/or Thromboxanes
3) IL-1 = Collagenase/MMP
4) Lipooxygenase = Luekotrines
5) iNOS = NO
6) TNF-a
7) Adhesion molecules

And of which all lead to negative feedback loops, which are incredibly hard to break, once they start. Which is why a cytokine storm is so incredibly hard to control and the treatment is palliative and supportive.

These negative feedback loops then lead to more IL-1 and PGE2, ROS and oxidative stress, and more TNF-a and CRP. Viscious little cycle, and genetics absolutely play a part. As the triggers are highly variable and modifiable, and the genetic expression from one individual to another is as well.

All of this then leads to pain, inflammation, cardiovascular disease, neurodegeneration, Insulin resistence, Autoimmune disease, Rheumatic disease, and yes.....cancer too.

So compared to the controls considered normal, and those with Autism with higher then normal levels of microglial activation, and then those of us with CFS/ME, what predisposition exists, and do they differ with the trigger? How come I have been functional albeit I have had trouble with infections my entire life, but functional up until a certain point, and then I was knocked flat.
On your list of cytokines in a viscious cycle, you list TNF-alpha and I wanted to say that DHEA has a significant impact of breaking that viscious cycle. This is according to www.lef.org. I find it helps me tremendously. I take 75mg/day and it 'corrects me' - I can feel it (very good) within 15 min and I also feel very bad w/o it.I also take very high antioxidants (2g C/day, 1g E/day). And I take 1g olive leaf extract to prevent gut pathogens (and the need for antioxidants against those).
 

Lotus97

Senior Member
Messages
2,041
Location
United States
I seem to have Asperger's syndrome. At least 2 online tests I took say I have Asperger's (albeit a mild case). I think the tests are as accurate a therapist or psychiatrist's diagnosis. I started a blog a few weeks ago with some multimedia resources and links to the online tests.
http://forums.phoenixrising.me/inde...ist-introvert-add-adhd-ocd-neurotypical.1381/

I was curious about Asperger's SNPs and I found they did a study comparing SNPs of people with Asperger's to people with other forms of autism.
http://www.sciencedaily.com/releases/2009/07/090715101427.htm
Asperger Syndrome, Autism, And Empathy: Study Links 27 Genes

The research found that single nucleotide polymorphisms (SNPs) in 27 out of the 68 genes were nominally associated with either AS and/or with autistic traits/empathy. 10 of these genes (such as CYP11B1) were involved with sex steroid function, providing support for the role of this class of genes in autism and autistic traits. 8 of these genes (such as NTRK1) were involved in neural growth, providing further support to the idea that autism and autistic traits could result from aberrant patterns of connectivity in the developing brain. The other 9 genes (such as OXTR) were involved in social behaviour, shedding light on the biology of social and emotional sensitivity.

Dr Chakrabarti commented: "These 27 genes represent preliminary leads for understanding the genetic bases of AS and related traits, such as empathy, in the general population. All of these are good candidates for independent replication studies in both low and high functioning autism samples. 5 of the genes we found have been previously reported in autism, but the other 22 have never before been reported in association with AS, autistic traits or empathy. We now need to test models of how these genes interact and construct 'risk' models for the development of AS."

Professor Baron-Cohen added: "We chose to look at the genetics of AS because all other genetic studies have focused on classic autism, which can include learning difficulties and language delay. AS is a more 'pure' condition because these other factors are absent. These new results represent a significant advance over our previous work in showing that the sex steroid hormones (e.g. testosterone and oestrogen) influence social development and autistic traits. The new study also confirms earlier reports that other molecules (such as oxytocin) are important in understanding autism, autistic traits, and empathy."