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Systolic BP Polygenic Risk Score With Chlorthalidone Response
Quick Takes
- Systolic blood pressure (SBP) polygenic risk score (PRS) was associated with SBP response to chlorthalidone, but not lisinopril, using two independently generated scores.
- Individuals at higher genetic risk of elevated SBP had a reduced SBP response to chlorthalidone after 6 months.
- Furthermore, it was observed that a higher SBP PRS was also associated with multitreatment nonresponse.
Study Questions:
What is the ability of a systolic blood pressure (SBP) polygenic risk score (PRS) to predict antihypertensive treatment (AHT) response and apparent treatment-resistant hypertension (aTRH)?
Methods:
The investigators conducted this analysis from a subset of Black GenHAT (Genetics of Hypertension Associated Treatments) participants randomized to the treatment groups of either chlorthalidone (n = 3,745) or lisinopril (n = 2,294), with genetic data available from a prior genetic association study. The GenHAT study was an ancillary pharmacogenomics study of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). The current study's objective was to examine the association of the SBP PRS to AHT response over 6 months, as well as to examine the predictive accuracy of the SBP PRS with aTRH. The current analysis took place in February 2023, with additional analyses conducted in July 2024. An SBP PRS (comprising 1,084,157 genetic variants) stratified as quintiles and per standard deviation.
The primary outcome was change in SBP (ΔSBP) and diastolic BP (ΔDBP) over 6 months. aTRH was defined as the use of three AHTs with uncontrolled hypertension (HTN) at year 3 of follow-up or taking ≥4 AHTs at year 3 of follow-up, regardless of BP. Baseline demographics were compared across PRS quintiles using Kruskal-Wallis or χ2 tests as appropriate. The least-square means of BP response were calculated through multivariable adjusted linear regression, and multivariable adjusted logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for aTRH.
Results:
Among 3,745 Black GenHAT participants randomized to chlorthalidone treatment, median (interquartile range) participant age was 65 (60-71) years, and 2,064 participants (55.1%) were female. Each increasing quintile of the SBP PRS from 1 to 5 was associated with a reduced BP response to treatment over 6 months. Participants in the lowest quintile experienced a mean ΔSBP of -10.01 mm Hg (95% CI, -11.11 to -8.90) compared to -6.57 mm Hg (95% CI, -7.67 to -5.48) for participants in the median quintile. No associations were observed between the SBP PRS and BP response to lisinopril. Participants in the highest PRS quintile had 67% higher odds of aTRH compared to those in the median quintile (OR, 1.67; 95% CI, 1.19-2.36). These associations were independently validated.
Conclusions:
The authors report that Black individuals with HTN at a lower genetic risk of elevated BP experienced an approximately 3.5 mm Hg greater response to chlorthalidone compared with those at an intermediate genetic risk of elevated BP.
Perspective:
This study reports that the SBP PRS was associated with SBP response to chlorthalidone, but not lisinopril. Individuals at higher genetic risk of elevated SBP had a reduced SBP response to chlorthalidone after 6 months. Furthermore, it was observed that a higher SBP PRS was also associated with multitreatment nonresponse (aTRH). These findings support a potential clinical utility of PRS in pharmacogenomic studies of AHT in the hope of guiding more personalized strategies in the future. However, randomized clinical trials are needed to systematically evaluate the implementation of SBP PRS in clinical practice and compare its efficacy in guiding HTN treatment and risk stratification against conventional standard of care.
Clinical Topics: Prevention, Statins, Hypertension
Keywords: Blood Pressure, Chlorthalidone, Hypertension, Risk Assessment
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