ASH 2015

How do genes influence the development of chronic idiopathic thrombocytopenic purpura?

Prof Jenny Despotovic - Texas Children's Cancer Center, Houston, USA

You’ve been looking at the way genes influence chronic ITP. Can you explain to me why you were interested in doing this and what, in fact, you decided to do?

Sure. Chronic ITP has not been historically thought to be a genetic disorder, meaning inherited from family members, but there’s clear heterogeneity in presentation, who gets ITP versus who doesn’t and also disease severity, who becomes chronic versus gets better, who responds to various treatments. So we thought we would look and see if there’s a genetic basis or a variation in your DNA that would explain those differences.

Now, you were using whole exome sequencing, weren’t you?

Correct.

What was the theory behind that and why did you go for that approach to looking for genetic variants?

Well historically all we had available was to think about potential candidate genes that might be involved in certain pathways and sequence those areas. But that really limits you to just what the investigator can come up with as far as pathophysiology. But now that we have next generation sequencing, or whole exome sequencing, we actually can look at all of the active areas of the DNA and find things we didn’t even know we were looking for.

Can you tell me about the study, what did you do?

What we basically did was we collected a cohort of DNA samples from children with ITP, chronic ITP, which at that time was defined as ITP lasting longer than six months. 173 of the samples came from the North American Chronic ITP Registry and another 90 came from the Platelet Disorder Centre at Cornell in New York. We brought them down to Baylor where we have the Human Genome Sequencing Centre where we’re able to do this high technology next generation sequencing. What we did was we ran all the samples through the sequencing, identified all the different variants of which everyone has hundreds of thousands and basically looked for the ones that were damaging, meaning causing protein coding problems or big problems in the gene of interest.

It sounds like a needle in the haystack job.

Well, it’s a needle in the haystack job but then what you do is compare to controls because we all have mistakes in our DNA. So then we take a cohort of healthy controls which we got from the Atherosclerosis Risk in Communities cohorts, about 5,000 healthy volunteers through the University of Texas. So a lot of them we can eliminate as not important because they are common in lots of different populations. What we were looking for were ones that were higher frequency in our population and ITP cases.

And what did you find?

In that case we found 188 damaging variants that were higher frequency in our cases versus the control population. But we focussed really on the ones that are involved in cellular or T-cell mediated ITP.

What came out of this, then, in a nutshell?

In a nutshell we found the most significant finding was we found a variant in the gene called IFNA17 that codes for interferon alpha 17. We found that it was present in 44%, 44% of our ITP cohort had a variant in this gene. One variant in particular, 26% of our cohort had that variant compared to 5% of healthy controls.

OK, a pretty big signal then. Putting this into the practical domain, are you able to put that to some sort of clinical usefulness, do you think?

Eventually down the road that’s the goal. So the whole idea of looking for these things is what can we do with them, how can we make treatment better? Right now we have several treatments available for people with ITP, some of them work in some patients and not in others. We have no way to tell families when someone presents with ITP whether they’re likely to become chronic or their disease resolves. So finding these is so important because eventually we want to be able to tell families we tested for this gene, it’s positive, you’re more likely to have chronic or you’re more likely to have a disease that goes away on its own.

Could you, in fact, select a treatment on the basis of those genetic findings?

That’s the goal. So the treatment response phase of this analysis has not been completed yet but the goal is that we identify good risk factors for various treatments and are able to avoid unnecessary side effects in patients in which a drug is not very likely to work for them.

Of course you might already have some useful drugs in the armoury, but what about developing new ones on the basis of this genetic knowledge?

That’s down the road too, those are all things we’re thinking about.

So what should doctors take home from your study, this very fascinating study, precise study, about genes?

Really this is the first time this approach has ever been taken in a cohort of people with ITP. Again it’s previously thought that it was not a genetic disorder. We don’t understand a lot about the biology of why someone gets ITP and so what the take home message is is that we’re making really great progress. This is a great first step at understanding why an individual develops ITP versus somebody who is exposed to the same risk factors who does not. Also, the goal will be that we can risk stratify better, we can optimise therapy better, tailor therapy directly and hopefully down the line target therapy directly to specific mutations.