ImportanceThe clinical utility of polygenic risk scores (PRS) for blood pressure (BP) response to antihypertensive treatment (AHT) has not been elucidated.ObjectiveTo investigate the ability of a systolic BP (SBP) PRS to predict AHT response and apparent treatment-resistant hypertension (aTRH).Design, Setting, and ParticipantsThe Genetics of Hypertension Associated Treatments (GenHAT) study was an ancillary pharmacogenomic study to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT, which enrolled participants aged 55 years or older with hypertension (HTN) starting in February 1994, completed follow-up in March 2002. The current study was conducted from a subset of Black GenHAT participants randomized to the treatment groups of either chlorthalidone (n = 3745) or lisinopril (n = 2294), with genetic data available from a prior genetic association study. 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.ExposureAn SBP PRS (comprising 1 084 157 genetic variants) stratified as quintiles and per SD.Main Outcomes and MeasuresThe primary outcome was change in SBP (ΔSBP) and diastolic BP (ΔDBP) over 6 months. aTRH was defined as the use of 3 AHTs with uncontrolled HTN at year 3 of follow-up or taking 4 or more 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 and 95% confidence intervals for aTRH.ResultsAmong 3745 Black GenHAT participants randomized to chlorthalidone treatment, median (IQR) participant age was 65 (60-71) years, and 2064 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 (odds ratio, 1.67; 95% CI, 1.19-2.36). These associations were independently validated.Conclusions and RelevanceIn this genetic association study, 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. SBP PRS may also identify individuals with HTN harboring a higher risk of treatment-resistant HTN. Overall, SBP PRS demonstrates potential to identify those who may have greater benefit from chlorthalidone, but future research is needed to determine if PRS can inform initiation and choice of treatment among individuals with HTN.

中文翻译：

---

收缩压多基因风险评分与氯噻酮反应的效用


重要性多基因风险评分 （PRS） 对血压 （BP） 对抗高血压治疗 （AHT） 反应的临床效用尚未阐明。目的探讨收缩压 BP （SBP） PRS 预测 AHT 反应和表观难治性高血压 （aTRH） 的能力。设计、设置和参与者高血压相关治疗的遗传学 （GenHAT） 研究是抗高血压和降脂治疗预防心脏病发作试验 （ALLHAT） 的辅助药物基因组学研究。ALLHAT 从 1994 年 2 月开始招募 55 岁或以上患有高血压 （HTN） 的参与者，并于 2002 年 3 月完成随访。目前的研究是从随机分配到氯噻酮 （n = 3745） 或赖诺普利 （n = 2294） 治疗组的 Black GenHAT 参与者子集进行的，遗传数据可从先前的遗传关联研究中获得。本研究的目的是检查 SBP PRS 与 6 个月内 AHT 反应的关联，以及检查 SBP PRS 与 aTRH 的预测准确性。目前的分析于 2023 年 2 月进行，并于 2024 年 7 月进行了额外的分析。主要结局和测量主要结局是 6 个月内 SBP （ΔSBP） 和舒张压 （ΔDBP） 的变化。aTRH 被定义为在随访第 3 年使用 3 次 AHT 且 HTN 不受控制，或在随访第 3 年服用 4 次或更多 AHT，无论血压如何。酌情使用 Kruskal-Wallis 或 χ2 测试在 PRS 五分位数之间比较基线人口统计数据。 通过多变量调整线性回归计算血压反应的最小二乘均值，并使用多变量调整 logistic 回归计算 aTRH 的比值比和 95% 置信区间.结果在随机分配至氯噻酮治疗的 3745 名 Black GenHAT 参与者中，中位 （IQR） 参与者年龄为 65 （60-71） 岁，其中 2064 名参与者 （55.1%） 为女性。SBP PRS 从 1 到 5 每增加五分之一，与 6 个月内对治疗的血压反应降低相关。最低五分位数参与者的平均 ΔSBP 为 -10.01 毫米汞柱（95% CI，-11.11 至 -8.90），而中位数五分位数参与者的平均 ΔSBP 为 -6.57 毫米汞柱（95% CI，-7.67 至 -5.48）。未观察到 SBP PRS 与赖诺普利的 BP 反应之间存在关联。与中位五分位数的参与者相比，最高 PRS 五分位数的参与者的 aTRH 几率高 67%（比值比，1.67;95% CI，1.19-2.36）。这些关联都经过了独立验证。结论和相关性在这项遗传关联研究中，与处于血压升高中等遗传风险的黑人相比，血压升高遗传风险较低的 HTN 黑人个体对氯噻酮的反应约为 3.5 毫米汞柱。总体而言，SBP PRS 显示出识别可能从氯噻酮中获得更大益处的人的潜力，但需要未来的研究来确定 PRS 是否可以为 HTN 患者的治疗开始和选择提供信息。