NEW YORK – New research points to the possibility of using polygenic risk scores (PRS) established for predicting systolic blood pressure to distinguish between individuals with enhanced or diminished response to an antihypertensive drug called chlorthalidone.
"These findings provide a proof of concept for the potential clinical utility of PRS in pharmacogenomic studies of [antihypertensive treatment] in the hope of guiding more personalized strategies in the future," senior and corresponding author Nicole Armstrong, an epidemiology researcher at the University of Alabama at Birmingham (UAB), and her coauthors wrote in JAMA Cardiology on Wednesday.
As part of the "Genetics of Hypertension Associated Treatments" (GenHAT) effort, researchers from UAB, the Medical College of Wisconsin, and elsewhere looked at potential ties between polygenic contributors to systolic blood pressure and responses to two antihypertensive treatments: chlorthalidone and lisinopril.
The team's analyses focused on 6,039 African American hypertension patients aged 55 years or older, randomized to receive one of the two drugs. The results suggested that two established PRS for systolic blood pressure could help not only in predicting response to one of the drugs — chlorthalidone — over six months of treatment but also in flagging participants prone to apparent treatment-resistant hypertension over three years of follow-up.
In the subset of 3,745 participants receiving chlorthalidone, for example, individuals grouped in the lowest systolic blood pressure risk group by PRS had enhanced response to chlorthalidone. On the other hand, participants at highest polygenic risk of high blood pressure had a more muted response to the treatment, with those at intermediate systolic blood pressure risk by PRS falling in between in terms of chlorthalidone treatment response.
"Our results suggest that if genetic data were available to generate a [systolic blood pressure] PRS, it could be valuable for patients starting a thiazide diuretic, like chlorthalidone," Armstrong said in an email. "This information could also encourage better treatment adherence and help address treatment reluctance to those in the higher PRS quintiles."
Although each group showed some reduction in blood pressure on the treatment, Armstrong explained, the group classified at lowest polygenic risk had average systolic blood pressure measures that were almost 5 mm Hg lower than their counterparts in the high risk PRS group after six months of chlorthalidone treatment — a blood pressure difference that coincides to close to 10 percent lower risk of blood pressure-related cardiovascular events.
Likewise, the investigators saw a 67 percent uptick in apparent treatment-resistant hypertension in individuals grouped at high risk of elevated systolic blood pressure by PRS compared to individuals in the intermediate PRS group. They also went on to validate the PRS associations with treatment resistance in individuals with African- or European ancestry from the "Reasons for Geographic and Racial Differences in Stroke" (REGARDS) study.
"While our analysis primarily focused on Black participants due to the nature of the available genotyped data, we included Black and White participants from the REGARDS study to validate our main findings on [apparent treatment-resistant hypertension (aTRH)]," Armstrong explained, noting that "both Black and White participants were significantly more likely to develop aTRH if they were in the highest quintile of the SBP PRS and less likely to develop aTRH if they were in the lowest quintile compared to those in the median quintile."
She cautioned that the PRS scores used in the study are not yet actionable in a clinical setting, though they may be developed further to identify hypertension patients who may require combination treatment, enhanced monitoring or higher-than-usual doses to achieve ideal blood pressure control.
"Randomized clinical trials are necessary to systematically evaluate the implementation of these types of PRS in clinical practice, as well as compare their efficacy in guiding hypertension treatment and risk stratification against conventional standard care practices," Armstrong explained. "Given the potential benefits highlighted in this study, we hope that these scores can be applied to other populations and antihypertensive treatments in the future."
In a related editorial in JAMA Cardiology, Northwestern University Feinberg School of Medicine's Sadiya Khan suggested the new work "highlights the need to consider the concept of precision medicine and rigorously evaluate potential clinical uses of PRS in diverse samples as more and more of our patients pursue assessment of genetic data and interest in PRS remains high."