Polygenic risk scores
Prof Qureshi discusses polygenic risk scores and other genomic technologies that may be available in the future.
Hello, everybody. My name is Imran Rafi. I’m a GP in Surrey. And it’s with great pleasure we have Professor Nadeem Qureshi who’s a clinical professor of primary care in Nottingham, as well as co-director with Professor Joe Kai of the stratified medicines research group in Nottingham. Nadeem, welcome and thank you very much for joining us. So we’ve sort of been talking about familial hypercholesterolaemia from case finding to using NICE guidelines to cardiovascular risk assessment. And, with all the searches that we do in primary care, we’re, undoubtedly, going to pick up patients who don’t have FH that may have raised cholesterols and may still be at cardiovascular risk.
Can you just sort of talk a little bit more around this, particularly, around sort of polygenic assessment? So, yes, you can find patients that you’ve sent for assessment that have got really high cholesterols. And they don’t actually have the familial hypercholesterolaemia mutation on the genetic test, but, more recently, from research at UCL, they found that these patients have a polygenic type of hypercholesterolaemia. So, similar to the multiple genes that decide if you are tall or short, these are several genes that slightly increase the cholesterol, but, collectively, they can actually cause a really high cholesterol. And, in rare circumstances, they can be as high as in familial hypercholesterolaemia.
And, similar to familial hypercholesterolaemia, you’ll treat them with high-potency statins and other drugs. More often, they’ll only have a slight effect on the cholesterol. And then it’s not current practice, but you can see, in the future, similar to how we use, say, diabetes or blood pressure or overweight or ethnicity, this could be another risk factor we need to take into account when we’re actually assessing patients. And so, when we’ve got someone with a strong family history, and they’ve also got a high polygenic score, then we might consider that we should more aggressively treat their risk factors, particularly, their cholesterol management.
OK, does family history not tell us something about the genes that might be running through the family, as opposed to a separate polygenic [INAUDIBLE] So, yeah, it’s just the family history more often tells you about the single gene defects like familial hypercholesterolaemia. But, when you’re looking at cardiovascular risk assessment, you’re combining various different risk factors. So what I was indicating there was that, as well as looking at the family history, you might also look at polygenic as another separate risk factor, as well as a family history, as well as obesity, as well as ethnicity. So family history is incorporated within the some of the risk assessment tools we have say, for example, QRISK.
So do you envisage when we have further detailed knowledge about polygenic risk scores that they’ll be incorporated within such risk templates? Well, they might be. They’ve already been incorporated in cancer templates. So it’s possible. This is really looking at the future, how things go. Some people believe polygenic will replace family history, but family history is a complex interaction of environment and genes. So I think it still will have a role in the future, but we might have more novel markers like polygenic and other things. So, for instance, people got very excited about a high-sensitivity CRP as another novel marker, but that’s for the future. At the moment, it’s probably still in its infancy how we could use this.
That’s very helpful. Thank you. And the other aspect really is identifying relatives of those cases who have been diagnosed as having FH. Could you just sort of expand a little bit more about how we manage these patients? So, basically, when you start with an index case, you identify further relatives by genetic testing. That’s how NICE recommend it, but you can also use cholesterol. And the patients are actually managed exactly the same as the index case. If they’ve got raised cholesterols, you treat the cholesterol level to bring it down to a safe level. One of the issues there is, when you’re cascading, as it’s called, to other relatives, you can go down to children.
And that’s quite challenging because, generally, under 10, you wouldn’t give them drug therapy. So it’s just giving them lifestyle advice. And the problem there is that, actually, you don’t really know when the patient’s severity is so severe that you need to start the therapies. We say 10, but NICE and others do say, if their family history indicates that a father or uncle started developing heart disease in their 30s, you might want to start earlier, but that requires real expert input, not just from a familial hypercholesterolaemia specialist, but also a paediatrician with an interest in FH. But you, as a GP, have a role in dietary and general health prevention advice, as you will do for the parents.
OK, and, to be clear, the cascade testing would happen in lipid clinics or specialist clinics set up to look at those? Yeah, it will be in a lipid specialist clinic and, in some cases, in genetic clinics, but, mainly, lipid specialists, often, run by specialist nurses going out in the community, either contacting the relatives through the index case, the person who’s come in, or, more rarely, but becoming more common, directly contacting the relatives. And that’s called direct or indirect cascade screening. And one last point, I’m sure you’re aware about over-the-counter, direct-to-consumer testing. And I wonder what your thoughts are around that, as opposed to testing through the NHS.
One of my concerns is that there’s not the robust quality control of over the counter. So, for instance, as we do next-generation sequencing, in our own research, we’ve found up to 8% of patients have something called a Variant of Unknown Significance, which is we haven’t really sure if it’s the real condition or if it’s a benign condition. When you have over-the-counter testing, often, they’ve not done the robust evaluation of these VUSes. So they could be included. They could be excluded. And so it hasn’t got the quality control. So, if a patient does have a test over the counter, they do need to have it retested through the NHS. OK, that is really helpful. Nadeem, it’s fantastic.
Thank you very much for providing us with such fantastic information around this important topic. You’ve mentioned a number of resources, which we’ll capture, and we’ll put up on the platform here for us to use in primary care. But, for now, I just want to say thank you so much for all your input. And, if there are any comments or queries, please do fill the comments box below, and we’ll be happy to respond to your comments. Thank you. Thank you, Nadeem.
In the third part of the interview with Prof Qureshi, he covers polygenic risk scores, DTC testing, pharmacogenomics in the context of how management of genetic diseases is changing.
Patients may bring in over the counter genomic reports through direct to consumer testing (DTC). For example there may be pharmacogenomic data on the prescribing around statins. This may be challenging in trying ascertain the validity of the results from such testing. The RCGP have issued guidance through a position statement. More information on DTC will be provided in week 3 of this course
There is a lot of work being done in terms of FH through service delivery by NHS England.
Through research work and studies incidental findings may be reported back to the patient or possibly the GP. For example the The Our Future Health project, (formerly known as the Accelerating the Early Detection of Disease project) is considering the potential findings from whole genome sequencing and what is fed back to the patient or GP.
As we have seen, polygenic risk scores will develop and be increasingly used in risk stratification. However its clinical utility will need defining over time. The PHG Foundation has useful information:
- Polygenic risk scores general background
- Polygenic scores in cardiac disease
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