Anybody with high blood pressure wants to know why it is high. We hear the word ‘genetic’ quite often, when we talk about causes of hypertension. However, how often is it true? Is high blood pressure pre-determined? What can be done with inherited hypertension? What does science already know and what is yet to be discovered?
Bloodpressure.Me Editor talked to Dr. Helen Warren, a Senior Lecturer in Statistical Genetics at Queen Mary University of London. Dr. Warren was one of the authors of the recently published study in the genetics of blood pressure, the largest ever done. In this study, researchers of over 100 universities across the world contributed data to this joint work.
Dr. Warren, in the media publications on this study, you are cited to say that “we have now revealed a much larger proportion of the genetic contribution to blood pressure than was previously known.” Please elaborate.
In total, our study reports over 2,000 independent genetic signals for blood pressure (BP). The number of genetic regions that we have been discovering for BP has been accumulating over the past ~17 years, from the very first genetic study like this for Hypertension back in 2007 (which wasn’t successful in finding anything, at first!), all the way up until these latest study results today.
Were there many studies in this area?
There have been many different BP genetic studies over these past ~17 years, and our list of the number of genes we’ve been identifying has been growing. At the end of each study, we quantify how many of the genetic signals we have now discovered, compared to the overall total of genetic signals that we expect there to be. And of course, this quantity is continuously increasing from one study to the next.
If you were to compare this process with something we know from outside healthcare, what would it be?
It is a bit like one of those charity fundraising thermometers, where the top level of the thermometer indicates the maximum amount expected, and we are hoping to see the bar of the thermometer gauge level gradually increasing closer and closer towards the ultimate total!
Please explain to a hypertensive person why this study’s results are significant?
A very simple explanation: we are excited to report here, that all the genetic variation we have identified in total for BP, provides the clearest picture so far of the overall genetic architecture of BP, and we have revealed much more of the genetic variation underlying BP regulation, compared to any of the previous studies.
And now a more detailed, technical explanation, please.
Every different trait or disease, whether it is BP, or BMI, or Diabetes, has a different genetic make-up, what we call its genetic architecture…in terms of firstly, how heritable it is (ie the ratio of the genetic contribution to the disease vs the influence of lifestyle environmental risk factors) and also how many different genetic signals are involved.
Different traits will have different numbers of genetic signals, and some more than others. Our genetic studies show that BP is a highly polygenic trait, meaning that it is influenced by thousands of different genetic variants, each with a small individual effect on BP levels.
How likely is it to inherit high blood pressure?
The overall heritability of BP has been previously estimated from family studies or twin studies to be ~30%.
When we refer in our study specifically to the “proportion of the genetic contribution to blood pressure”, we need to first estimate the % for the “genetic contribution” of BP, in terms of the heritability that is due to all single genetic variants of common-frequency in our European-ancestry population that we are analysing in our whole dataset. In our study we have estimated this to be e.g. ~17% for systolic BP.
Secondly, we need to then estimate the % of variance in the BP measurement levels within our cohort dataset population that are explained by all the genetic variation associated with BP that we have identified. Our optimal polygenic risk score for systolic BP explains ~11% of the variation in the systolic BP trait.
So then our final result is the ratio of these two % calculations, i.e. the “proportion of the genetic contribution” that we have now revealed for BP is ~11%/17% = 64%. So we state in our paper that we have revealed >60% of the genetic contribution to BP.
Back in 2018, our previous BP-genetics publication reported the proportion to be ~27%, after all the new genetic regions that had been identified in that 2018 study. So our result today of ~64% is more than double the previous 2018 results of 26.8% for systolic BP.
What will it mean to hypertensive patients?
At the moment, genetics is not used at all within the clinical guidelines for Hypertension. The BP-lowering drugs that we are prescribed are simply decided according to e.g: how high our BP measurement level is; whether we’re male or female; our age; our ancestry; any other diseases we may have; and of course any other treatments we may be taking.
But we are hoping to demonstrate some clinical utility of the results of our genetics research. It takes a long time for any research to be translated into clinical practice, a long journey “from bench to bedside”, as we say, in the laboratory.
How do you think the results of this study may be used?
One way that our results can be used, is that some of the new genes identified in our study, may be able to lead towards potential new drug treatments. Despite the many different antihypertensive drugs on the pharmacy shelves, and despite the rapid advances in research, unfortunately, still, only about half of patients prescribed antihypertensive drugs actually reach a lower, controlled BP level. So we still need improved drugs for treating hypertension, and discoveries of new genes may help in this direction.
And besides the medications?
Another way that our results can be used, is in patient risk stratification. Our study generated polygenic risk scores, which combine the effects of all genetic variants together to predict blood pressure and risk for hypertension.
For example, these risk scores show that individuals with highest genetic risk have mean systolic BP levels which are ~17 mmHg higher than those with lowest genetic risk, and a 7-fold increased risk of hypertension.
Therefore, these polygenic risk scores can discriminate between patients according to their hypertension risk, and reveal clinically meaningful differences in their blood pressure. We are making our polygenic risk scores data publicly available. There are many different potential applications of genetic risk scores, so it will be exciting to see how our blood pressure scores can be used to address more clinically relevant questions in the future.
Could you explain what these polygenic risk scores are?
BP is a highly polygenic trait, meaning that it is influenced by thousands of different genetic variants, and each of these genetic variants will only have a small, individual effect on increasing or decreasing BP levels.
However, if we combine together all the effects of all associated genetic variants into one single aggregated risk score, adding up the effects across all variants over the whole genome, which we call a polygenic risk score, this score explains much larger effects on BP.
Is it what they call genetic profiling?
Yes, we can think of this as genetic profiling. Each of us has a unique genetic profile. We are all carriers or non-carriers of different genes. If we consider the risk variants, as being all the genetic variants that we have identified which increase our BP levels, then some of us will carry more of these than others. So a polygenic risk score essentially gives each of us a score, according to how many risk variants we carry.
We can then look at the distribution of the BP polygenic risk scores (PRS) within a population, and consider those at the top end of the distribution with the highest scores as having the highest genetic risk of hypertension (high BP), vs those at the bottom end of the PRS distribution with the lowest scores as having the lowest genetic risk.
How are the polygenic risk scores used?
These PRS may become a very useful tool for patient stratification. Knowing someone’s genetic risk score, would enable a doctor to know if the patient was in the high genetic risk group.
Our study results show that, if we compare individuals in the top decile in the top 10% of the PRS distribution in the highest genetic risk group vs those in the bottom decile in the lowest 10% of the PRS distribution in the lowest genetic risk group, there is a difference of ~17 mmHg between their average systolic blood pressure levels.
Furthermore, individuals in the highest genetic risk group have 7 times greater odds for the risk of Hypertension. This will equivalently also translate into much higher odds of other cardiovascular diseases too.
So the new PRS that we generate from our study performs very well for patient stratification and can successfully discriminate between high vs low risk groups, with very large, clinically meaningful differences in the BP levels between genetic risk score groups.
What are the benefits of knowing our own genetic risk?
A huge benefit in knowing our genetic risk, is that our genes are fixed at birth. So our genetic risk score is the same fixed value throughout our life. Therefore, if we calculated people’s genetic risk scores earlier in life, before we are say middle-aged, when other lifestyle risks tend to increase with age…then doctors and clinicians would be able to target patients at higher genetic risk, and monitor them more closely, or recommend earlier lifestyle or therapeutic interventions…in order to help reduce their BP, before their higher BP may begin to impact their health, and hence reduce their risks of future cardiovascular disease.
Patient surveys also indicate that, if patients knew their genetic risk, they may be more compliant in taking recommended medications, for example, knowing how much more important it is to lower their BP and counterbalance their genetic risks.
So the clinical utility of PRS is patient stratification, which can enable targeted patient management.
As the performance of PRS continues to improve, they could also help to predict those at risk of high BP in the future, to aid earlier diagnosis.
The question ‘why me’ is posed very often in social media groups on high blood pressure. Can you answer it?
BP is influenced by both our genetics and our environmental / lifestyle risk factors. It is a balance. And we probably all have a slightly different ratio of whether our BP level is influenced more by our genetics, or by our lifestyle. We are all unique! If we consider any two people who have high BP, the reasons for their high BP could be very different.
One hypertensive patient could be carrying very little genetic risk, but they may be overweight, a smoker, with a poor diet. In contrast, the other hypertensive patient could be very fit and have a very healthy lifestyle, but hidden in the genes, and from family history, they could be highly susceptible to being at a high risk genetically of higher BP.
Hence, there are usually several reasons behind one’s high blood pressure?
A polygenic risk score is a combination of many different genetic variants, and essentially the score counts how many risk alleles we carry across all the BP-associated genes. So because BP is so highly polygenic, our high BP levels could be due to the combined effect of lots of small, individual risk genes all added together. So, in contrast to “monogenic diseases”, e.g. like Huntingtons that are caused only by one single gene, where you either are a carrier of that one single gene or not, then I don’t think the “why me” question is quite as straightforward for BP. All of us will carry some risk alleles for some of the BP-associated genes, it’s just a case of how many…
Then, in most cases it is a game of chance?
When genetics carries with it the 50:50 chance of which genes we inherit from our Mother, and which from our Father, it could all be seen as a game of chance.
However, instead of the “why me” question, with regards to what our level of genetic risk may be, or in other words, how high might our BP polygenic risk score be, perhaps the better question that patients could start asking is “what next”.
But what is possible to do if your high blood pressure is predetermined genetically?
There are many studies showing that improved lifestyle interventions can effectively help to lower our systolic BP levels by e.g. ~10 mmHg. So, if we were to find out that we were one of the unlucky ones, in terms of our genetic risk level, then I don’t think that should be the end of the story.
If, in the future, we can identify patients at higher genetic risk, earlier in life, clinicians can work with these patients in a tailored way, to focus on their lifestyle factors, in addition to antihypertensive treatments too, of course, and help patients to counterbalance their genetically influenced increased BP levels, by reducing their BP levels with improved lifestyle.
What do we already know about genetics of blood pressure, and we do not know yet?
We have now identified over 2,000 genetic signals for BP. So, from a research perspective, focusing on genetic discovery alone, we know a lot! Or, at least you could say, we have “found” a lot!
But yes, the problem lies, that we still don’t actually know enough about the actual function and underlying biological mechanism of many of these genes. And in fact, our genetic studies only actually indicate a particular genetic region on the genome that displays statistical significance for BP association. But there could be many different genes within this region, so we don’t know the actual causal gene influencing BP, or what its functional relationship is with BP.
In the early days, when only a few genes were identified in genetic studies, each gene would have been followed-up within the lab, for functional experiments, but now with over 2,000 genetic regions, there isn’t scope to investigate every single one in the lab! But we do hope that some of the candidate genes we suggest to prioritise, may be able to lead to new, improved drug targets for the treatment and prevention of hypertension for the future.
What are the limitations of your study?
The study that we have just published is a discovery analysis in European ancestry individuals only, and only testing genetic variants of common frequency. So two important directions that are required as future directions of research are (i) genetic studies of hypertension in non-European ancestries; and (ii) genetic analyses of rare genetic variants.
In your view, where to expect the next major breakthroughs in the research of genetic factors behind high blood pressure?
Our team also does lots of research on the pharmacogenetics of blood pressure, where we perform genetic analyses to search for genes which influence how well we respond to BP lowering drugs, i.e. our BP treatment response. Progress in the hypertension pharmacogenetics field could see major breakthroughs, if we can use genetic knowledge to aid the optimal selection of choosing the right drug for the right patient.
Overall, I would hope there could be some good breakthroughs in the clinical translation, for example seeing some useful applications of our BP polygenic risk scores, for progressing towards the goal of personalised medicine.
