AAN 2024 | Polygenic predisposition to hypertension predicts blood pressure treatment response
Shufan Huo, MD, PhD, Yale School of Medicine, New Haven, CT, explains her work studying the impact of polygenic predisposition to hypertension on blood pressure treatment response. Using participants from the All of Us research program, polygenic risk scores were calculated that summarized 732 genetic risk variants for hypertension. Participants were then categorized into low-, intermediate-, and high-risk groups. The research found that polygenic predisposition to hypertension correlated with treatment-resistant hypertension and an increased risk of stroke within three years of follow-up. Dr Huo hopes that the polygenic risk score can be employed as a screening tool in clinical practice to identify individuals at high risk of hypertension, therefore allowing for personalized treatment strategies and early intervention. This interview took place at the American Academy of Neurology (AAN) Annual Meeting 2024 in Denver, CO.
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Transcript
There has been a lot of research about polygenic risk for, let’s say, hypertension and the clinical outcomes. So we know that polygenic predisposition to hypertension can increase not just blood pressure values, but also the risk for other outcomes, even in participants that do not have clinical hypertension yet. So, this is already known. However, what was interesting for us to see was how this translates into a clinical application and specifically into treatment response...
There has been a lot of research about polygenic risk for, let’s say, hypertension and the clinical outcomes. So we know that polygenic predisposition to hypertension can increase not just blood pressure values, but also the risk for other outcomes, even in participants that do not have clinical hypertension yet. So, this is already known. However, what was interesting for us to see was how this translates into a clinical application and specifically into treatment response. Up to 20% of interindividual variety of blood pressure is attributed to genetics, but we don’t really know if this correlates with treatment response as well.
So, we investigated participants within the All of Us research program. It’s a large cohort that is still enrolling, but aiming to enrol 1 million US Americans and is funded by the NIH. All these participants receive full genotyping so we have available genomic data for all these participants. We calculated a so-called ‘polygenic risk score’, which summarizes all the known genetic risk variants for systolic blood pressure, or hypertension. In total there are 732 variants that we used to create this risk score. Based on this risk estimation of the polygenic risk score, we categorized the participants into low, intermediate and high genetic risk. Low is less than 20th percentile, intermediate 20 to 80th percentile, and high risk is above 80th percentile. We only included participants that were treated with antihypertensive medication. We wanted to see the effects of polygenic risk within this specific group of treated participants on several outcomes. The outcomes that we investigated were systolic blood pressure values (measured sequentially in the follow-up), treatment-resistant blood pressure (defined as systolic blood pressure above 140mmHg despite being on treatment, since all these participants were treated), and then the third outcome was stroke within three years of follow up. Then we conducted regression analyses.
Polygenic predisposition to hypertension correlated with increased values of systolic blood pressure for all comparisons; so for both for the intermediate versus low group comparison, but also for the high versus low group comparison. Similarly, we could see that polygenic predisposition to hypertension also correlates with treatment-resistant hypertension. This does not only reflect within the blood pressure values, but also with respect to clinical outcomes. We saw in the survival analysis that there was an increased hazard of stroke during the three-year follow-up as well. All these findings were validated in an independent cohort, the UK Biobank, and they found the same.
Translation that would make sense within clinical practice would be to use the polygenic risk score as a screening tool to identify high-risk subjects and maybe address personalized treatment strategies within the future. It’s one step and we don’t have the full genetic data available at this moment. But, since genotyping is becoming more and more available and also more affordable, we do think that this will be an avenue to pursue in the future.
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