A disease-associated gene desert directs macrophage inflammation through ETS2 [in IBD] 2024 Stankey et al

Abstract

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge.

By investigating an intergenic haplotype on chr21q22—which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis3,4,5,6—we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Open access, https://www.nature.com/articles/s41586-024-07501-1

 

Articles:

Bowel disease breakthrough as researchers make ‘holy grail’ discovery

https://www.theguardian.com/society...ease-hope-researchers-find-biological-pathway


Major cause of inflammatory bowel disease found

https://www.bbc.co.uk/news/articles/c1wwdd6v2wjo

 

https://www.nature.com/articles/s41586-024-07501-1

Also reported in The Guardian (UK):

https://www.theguardian.com/society...ease-hope-researchers-find-biological-pathway

 

Sorry for the duplicate post, I did a search before adding it but obviously picked the wrong terms.

 

Simple answer is I don't know if we will or won't. I suspect that as we are looking across the whole genome, some of our results will come from what are currently considered to be non-coding regions, but I have asked the question of the team, and will come back with an informed answer.

 

Hmm, no I don't think they're doing it right. Where are the questionnaires that ask overlapping questions, showing how it's all anxiety, and the dubious biased trials showing how it's an "aw shucks, it's gonna be one of those days isn't it?" attitude in the morning that makes the bowels feel like they hurt?

Did they even consider the mind-body-brain-Flying spaghetti monster connection? Not even a finger-painting group therapy where they explore their thoughts and beliefs about tubes and how it's what makes their tummies hurt?

One day, the biopsychosocial model of illness will have its first ever breakthrough. That day isn't today, or ever. But one day it will show its usefulness. You'll see!

 

Hmm. It. might indicate that in certain areas, like this one, people are constantly drawing inappropriate conclusions from in vitro studies that get fashionable for a while and then get replaced by another fashion.

I have not read the full article but the abstract reads like an advert for these researchers' favourite molecule causing everything. I don't see any crucial new data being presented. It has been clear for 30 years that these illnesses involve genetic thresholds for inflammation (and we know the dominant ones to be different for each condition). Finding expression of a protein in tissue is a very weak piece of evidence, since inflamed tissue tends to express a whole bang shoot of things for nonspecific reasons.

 

• It is a pity that their opening sentence is a reference to a putative increase in autoimmune disease when the conditions they are reporting on are not autoimmune diseases. You have to be fairly muddled to make a mistake like that.

 

I also understood the abstract and perhaps the whole paper to be more of an advertisement for functional genomics rather than anything else and that the authors don't call IBD an autoimmune disease. I suppose they might be applying for grants in this direction.

Apart from the genetic work, my naive understanding is that the authors implicated that pharmacologically MEK inhibition could be fruitful, but that they didn't actually produce any meaningful data. But their approach to from GWAS to pharmacological targeting seems sensible to me.

The authors seem to implicate that once the GWAS work is done, functional genomics can be helpful in understanding those leads and what role non-coding genetic associations could play. I can't claim to understand any of what is going on, but perhaps an avenue to possibly explore in Project ideas for DecodeME data if DecodeME unveils something.

 

My suspicion was correct, the Genetics Delivery Team confirm that DecodeME will "perform a genome-wide association study (GWAS) which covers both coding and non-coding regions of the genome (the later representing more 98% of the genome) rather than looking at specific regions. Actually, the majority of GWAS signals are located in non-coding regions. If we found a significant association within a region , coding or not, it will be investigated following the post-GWAS analysis plan."

 

Yes, well we have known that since the 1970s, when Brewerton sneakily made the first report of HLA-B27 being associated with Ank Spond. (he had seen some other people's data it seems).

In the paragraph they say "This high failure rate is mainly due to a lack of efficacy8 and reflects our poor understanding of disease mechanisms."

In reality the inefficacy mostly reflects very blinkered thinking by the fashionable dogma. The problem was not 'guesses' about treatments but organised PR campaigns by people, also with interests in grant money. Dozens of anti-T cell therapies were thrown at RA based on a theory that misinterpreted some data of mine on T cells being present in joints. It took me another five years to work out why it was B cells but it was obvious that nothing pointed to T cells.

And when we worked out why an anti-B cell approach might be good, it was based on detailed analysis of tissue specific control of macrophage maturation-exactly what these people think is a wheel they have re-invented, except that we had a logical sequence of arguments as to why specific pathways would link up. All these people seem to have done is measure some mediators in tissue (like my original observation of some T cells in tissue) and done some mouse manipulation, which doesn't look to me to be specific enough to be very helpful.

Point being that you need to understand the genetics and have a very detailed understanding of tissue processes. And we knew that in 1995. I wrote a review in Immunology Today about the role of tissue specific events in pathogenic mechanisms in Ank Spond that I suspect is still valid. These people seem to be blissfully ignorant of such things.

I put in grants for looking at the non-coding genetic basis for connective tissue cell maturation pathways in 1996. Nobody was interested because it wasn't T cells. The regulator they are interested in may well be part of the story but without taking note of all the stuff we already know I would be sceptical that it changes things that much. If it is relevant to half a dozen different diseases in different ways I suspect that it would be more useful to target the things that are specific to each disease rather than block some very basic macrophage maturation event, but maybe it will prove useful. I am not sure that blocking transcriptional regulators directly is that easy though.

Maybe they are just finally getting around to catching up with what happened 25 years ago!! I am just off to a lecture on killing B cells with CAR-T cells again. Same story, just now in fashion!!