Big New Genome Wide Association Study On Androgenetic Alopecia - Preprint

[InBeforeTheCure]

First of all very impressive work!

Thank you, thank you. If nothing else, this shows that we really know next to nothing about A.G.A. after all these years. I guess that's not surprising when there are less researchers in the whole field than in many cancer labs, and their annual funding is something like 6 dollars and a pair of free lab goggles.

Regarding the technical holdups I have no clue. I'm not really knowledgeable on this stuff. From what I have read (targeted) delivery and efficiency is still a problem.

There is already a drug running clinical trials for the androgen receptor though, for prostate cancer.

- ISIS-ARRx is a generation 2.5 antisense drug designed to inhibit the production of AR for the treatment of patients with prostate cancer. Because ISIS-ARRx can inhibit the production of all known forms of AR, including variants of the AR gene, this drug has the potential to be an effective treatment for all stages of prostate cancer, including prostate cancer patients who are resistant to current therapies.

That could be huge for prostate cancer. Hopefully we can have something for A.G.A. someday.

So then you could design it so it wouldn't interfere with AR in the brain, and then only apply the chemical to the scalp, and since AR is stopped at the gene it won't create any more.

It's actually stopped at the mRNA level -- the shRNA would induce cleavage of the AR mRNA. In the case of a chemical activated system though, you would need to continue applying the chemical (maybe every day depending on half-life) so that the shRNA is continuously transcribed.

It got renamed IONIS-AR-2.5Rx

Why, what's wrong with "ISIS"?

I guess it would be different in our case since heaps of people will want to buy it, so economies of scale should help.

You should probably write a whole academic article on it InBeforeTheCure and sell it to a company!

Well, I would have to have it before I could sell it, so...

 

[Takeela370]

Genes Potentially Affecting Androgen Metabolism

^^^ Genes involved in regulation of development and regulation of cell migration are a common theme in both the GWAS and in a list of genes affected by estrogen – perhaps the most potent reverser of A.G.A. – in hair follicles (again see the dissertation, pg. 108-109). Speaking of which, I put both the GWAS list and the estrogen list from that dissertation into WebGestalt for WikiPathways enrichment. The GWAS list was enriched for 42 pathways at p < 0.05, and the estrogen list for 22 pathways. Of the 22 pathways in the estrogen list, 14 pathways (63.6 percent) were also in the GWAS list. Given there are about 800 pathways in the WikiPathways database, this is quite a significant overlap. I'll admit that the estrogen list itself influenced me to pick FOSL2 for the GWAS list, but only one pathway in the WikiPathways database, "corticotropin-releasing hormone", contains it, and that one does show up in both lists. Anyway, these were the 14 pathways enriched for both the GWAS list and the estrogen list:

Focal Adhesion
EGF-EGFR Signaling Pathway
Muscle cell TarBase
Signaling Pathways in Glioblastoma
Corticotropin-releasing hormone
Regulation of Actin Cytoskeleton
Lymphocyte TarBase
TGF Beta Signaling Pathway
Endochondral Ossification
Androgen receptor signaling pathway
DNA damage response (only ATM dependent)
Senescence and Autophagy
Neural Crest Differentiation
MAPK signaling pathway

This myotonic dystrophy thing fascinates me though. It makes me wonder how much alternative splicing of genes involved in development are responsible for A.G.A. TARDBP, the closest characterized gene to that tricky Chr1 locus, is also an RNA splicing factor.

If you are interested in the FOSL2 pathway and the only one that contains it is corticotropin-releasing hormone, you should check out Astressin-B. You may have already seen this but it has been a favorite of mine since this article came out.

CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice

https://www.ncbi.nlm.nih.gov/pubmed/21359208

 

[Beowulf]

It's actually stopped at the mRNA level -- the shRNA would induce cleavage of the AR mRNA. In the case of a chemical activated system though, you would need to continue applying the chemical (maybe every day depending on half-life) so that the shRNA is continuously transcribed.

Gaaaah, so it's less of a cure and basically just a perfect maintenance method. I thought the chemicals were more like you put it on and the AAV turns on until it either dies out or you rub the chemical back into it. So if you can make it only active in specific cells is there a way to make it only effect the dermal papillae (which is where the ARs are located right?)?

Even if it was silencing all the ARs from the skin that seems like it would be fine, according to this article you'd probably cure acne as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763909/

Then again that probably isn't possible since skin is made up of lots of different cell types, unless skin has a particular combination of cell types, that would probably be alright. But as a complete amatuer who barely knows what he's talking about it doesn't seem like there's a way to make the AAV differentiate between the scalp/skin and some of the places where we probably still want ARs, but again what would I know? I'm sure you guys will probably prove me wrong. I wouldn't be surprised if I'm actually super confused about what the dermal papillae is and what dermal papilla cells are and which one has the ARs.

Otherwise it would probably be best to just drop the whole AAV thing and try the nano-particles instead.

Out of interest how long does the shRNA stick around for? It's like 6 years or something right?

Why, what's wrong with "ISIS"?

Hahaha! It's some silly stuff about how they got it from another company and then renamed the whole company. I guess it would have looked a bit weird if all the headlines said 'ISIS cures prostate cancer, moves onto baldness'.

 

[InBeforeTheCure]

If you are interested in the FOSL2 pathway and the only one that contains it is corticotropin-releasing hormone, you should check out Astressin-B. You may have already seen this but it has been a favorite of mine since this article came out.

CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice

https://www.ncbi.nlm.nih.gov/pubmed/21359208

For the record, here are the genes from the GWAS involved in the CRH pathway:

TGFB1
PLCG1
CTNNB1
FOSL2
TFAP2A

And for estrogen:

FOSL2
GJA1
NR4A1

Here's the WikiPathway for CRH:

So CRH modulates caspases, MAPKs, Akt, beta-catenin, TFAP2A, calcium, NF-kB, inflammatory cytokines, all of which have known effects on hair growth. Do you know which of these downstream pathways are more or less implicated in stress-induced hair loss, or has that not been determined?

As for FOSL2...Being part of the AP-1 complex, it will be activated by many different upstream signals, even though WikiPathways might not list them.

@Beowulf

You can also get a very long lasting or permanent effect without any kind of chemical activator, which of course would be very nice. You would use the chemical-activated system if you wanted more control over expression.

 

[Beowulf]

You can also get a very long lasting or permanent effect without any kind of chemical activator, which of course would be very nice.

If it won't effect the AR's in the genitals we should probably try to get a bunch of donations, and send someone your way to see if it works.

 

[Beowulf]

Turns out there aren't any adipocytes in the prostate.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1867111/

The only troubling thing is that there are adipocytes in bone marrow, but apparently transsexuals have a low chance of osteoporosis

https://www.ncbi.nlm.nih.gov/pubmed/9792472

We should seriously consider getting some money together and giving your AR shRNA AAV thing a try, it'll probably cure acne and slow aging to.

 

[InBeforeTheCure]

Beowulf, this is not the same as playing with research chemicals from China. How would you even get it anyway?

 

[Beowulf]

I thought you linked a site where you could just buy them. I mean you can just buy a 3d bio-printer online, and who knows why type of crazy crap you can get on the deep web. But hey I don't really know any thing anyway.

In any case you should probably write it up and sell it some company, the theory all sounds crystal clear... Even if current AAV treatments do cost $1,000,000, I'm sure some company out there could make it work or would at least be interested in buying your research.

 

[InBeforeTheCure]

I thought you linked a site where you could just buy them. I mean you can just buy a 3d bio-printer online, and who knows why type of crazy crap you can get on the deep web. But hey I don't really know any thing anyway.

They only sell to labs, for use in research. Some day though, something like that could be offered to the public and give at least a permanent maintenance cure for A.G.A.

In any case you should probably write it up and sell it some company, the theory all sounds crystal clear... Even if current AAV treatments do cost $1,000,000, I'm sure some company out there could make it work or would at least be interested in buying your research.

It's not my research and I don't own it. As non-biologists, you and I will have to wait and see if something comes along. The experts are well aware of AAV technology and don't need anyone to notify them about it.

 

[Beowulf]

It's not my research and I don't own it. As non-biologists, you and I will have to wait and see if something comes along. The experts are well aware of AAV technology and don't need anyone to notify them about it.

Oh well, thanks for humoring me anyway, it's made me feel a lot better.

When my exams are over I'll see what I can do to help you find all the missing links in the genes.

 

[Beowulf]

Here's heaps of other articles that are all about gene associations with Androgenetic Alopecia.

Out of interest did the GWAS only consider the associations between genes and baldness, or did they consider the connection between the genes as well?

 

[Armando Jose]

Nothing new.....
This is from the abstract of these 5 studies:

To date, molecular genetic studies have implicated 12 genomic regions in Androgenetic Alopecia and identified a number of candidate genes. The latter include those encoding the androgen receptor (AR), the histone deacetylases (HDAC) 4 and 9, and the WNT molecule WNT10A. However, the majority of contributing genetic risk factors still await identification.


Significant associations were confirmed for 29 SNPs from chromosomes X, 1, 5, 7, 18 and 20.


Since the response to androgens occurs within the follicle, it can differ. Androgen responses vary from stimulation (e.g. beard), no effect (e.g. eyelashes) to inhibition on areas of the scalp (androgenetic alopecia).



Our results highlight unexpected associations between early-onset Androgenetic Alopecia, Parkinson’s disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.


Thus, our study provides genetic evidence supporting an involvement of WNT signaling in Androgenetic Alopecia development.

 

[Beowulf]

It's just to back up the GWAS.

 

[InBeforeTheCure]

Here's heaps of other articles that are all about gene associations with Androgenetic Alopecia.

Out of interest did the GWAS only consider the associations between genes and baldness, or did they consider the connection between the genes as well?

In the OP, I posted the link to the full text, where they don't discuss connections between candidate genes in any detail. Or do you mean something else by this?

One thing I forgot to mention in my ramblings comes from that Heilmann 2013 paper you posted, where they show that the A.G.A. risk SNP rs7349332 is somewhat correlated with lower expression of WNT10A.

And here's another paper on Trps1 that I found: Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis

 

[Beowulf]

In the OP, I posted the link to the full text, where they don't discuss connections between candidate genes in any detail.

And it's basically impossible to know just how much one could increase the accuracy of the predictions by understanding the connections between the genes without reference to any other candidate genes?

But if we could find all the connections between the genes we could model them and then use a neural network AI to figure out the best way to balance them, or probably just figure it out ourselves. Then we could probably just test it out on ourselves to see whether we've identified them all or not.

 

[InBeforeTheCure]

And it's basically impossible to know just how much one could increase the accuracy of the predictions by understanding the connections between the genes without reference to any other candidate genes?

But if we could find all the connections between the genes we could model them and then use a neural network AI to figure out the best way to balance them, or probably just figure it out ourselves. Then we could probably just test it out on ourselves to see whether we've identified them all or not.

Unfortunately there are so many gaps in our knowledge that even basic inferences are hard to make. For example, after decades of research into A.G.A., nobody has actually looked at what the direct AR target genes in DPCs actually are, at least to my knowledge. There are studies showing genes upregulated/downregulated after DHT treatment, but it's not clear from that whether these are direct targets or indirect effects such as those induced by oxidative stress. TGF-beta1 is one such example -- DHT-induced upregulation of TGF-beta1 is dependent on oxidative stress, and in fact at physiological oxygen levels DHT actually inhibits TGF-beta1 in balding DPCs (see Figure 5 of this study).

Besides gaps in knowledge, another problem for making inferences is that in vivo findings in hair follicles sometimes differ from in vitro. For example, it's known that Wnt inhibits expression of FGF7 in DPCs in vitro, but upregulates it in vivo, perhaps due to crosstalk with other signaling pathways or genes regulated downstream of those. So when we look at microarray data and find that FGF7 is upregulated in balding DPCs, what inferences can we make about it? What's really happening in vivo? Now think about Twist1. Microarray studies find that Twist1 is upregulated in balding scalp, but since Twist1 is a Wnt target gene in DPCs, could the story be different in vivo there too?

Having said that, there is still a lot of information out there to play with. And by the way, this paper in Nature presents a method where the program looks for subnetworks of genes between GWAS loci to select likely candidate genes, which was part of my approach (though automated, objective, and much more sophisticated of course). I tried running it in R but got got an EOF error while running their example, so most likely their web service is down.

 

[Armando Jose]

genes upregulated/downregulated

Probably it could be different this gene regulation if the hair is in anagen or telogen phase. It is very complicated.

 

[Nadia1972]

We do not have to wait 20 years to see the first treatments in gene therapy. Treatments can appear even if they are not perfects
But if researchers don't interest in Androgenetic Alopecia,we will not wait 20 years but 30 years at least before we can see a gene therapy.
Cloning,i'll believe it when i see it

 

[Beowulf]

Having said that, there is still a lot of information out there to play with. And by the way, this paper in Nature presents a method where the program looks for subnetworks of genes between GWAS loci to select likely candidate genes, which was part of my approach (though automated, objective, and much more sophisticated of course). I tried running it in R but got got an EOF error while running their example, so most likely their web service is down.

So you could see this alright couldn't you?

 

[Beowulf]

I hope this is somehow helpful or at least relevant.