Hypertensive patients with greater genetic risk respond less effectively to treatment and are more likely to be treatment resistant in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
Introduction and Aims: Treatment-resistant hypertension (RHTN) patients have increased cardiovascular risks, and it is believed that RHTN may have genetic causes. It is also hypothesised that genetics may explain the inter-individual variability in antihypertensive drug response of patients.Our late...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
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| Series: | Clinical Medicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1470211825001253 |
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| Summary: | Introduction and Aims: Treatment-resistant hypertension (RHTN) patients have increased cardiovascular risks, and it is believed that RHTN may have genetic causes. It is also hypothesised that genetics may explain the inter-individual variability in antihypertensive drug response of patients.Our latest genome-wide association study (GWAS) for blood pressure (BP) reports 2,103 independent BP-associated genetic signals and provides powerful genetic risk scores (GRS). Therefore, we investigated whether BP-GRS are associated with RHTN and antihypertensive drug response, among treated hypertensive patients.We defined RHTN cases as patients with uncontrolled high BP despite the use of three or more antihypertensive drug classes, vs controls, who were defined as having controlled BP levels requiring the use of no more than three drug classes.BP-GRS were constructed for European ancestry patients from ASCOT for systolic (SBP), diastolic BP (DBP) and pulse pressure (PP). The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) recruited 19,342 hypertensive European patients between 40 and 79 years of age and randomised them to a beta-blocker (BB) or calcium channel blocker (CCB) arms. A total of 6,266 patients with available genetic date were included in ASCOT analyses.Change in BP response to treatment was considered within a sub-sample of ASCOT for patients on monotherapy treatment only (1,518 patients on BB, 1,780 on CCB). The BP drug response phenotype was calculated as the difference in their baseline vs on-treatment BP measurements. Methods: BP-GRS were constructed in all ASCOT individuals with genetic data. Each BP-GRS comprised all 2,103 published BP variants, weighted by their independent effect estimates from UK Biobank GWAS data only, so that increasing BP-GRS scores corresponded to increasing BP levels.We tested BP-GRS for association with: (i) RHTN, adjusted for: sex, age, BMI, diabetes, randomisation treatment arm and left ventricular hypertrophy; and (ii) BP response to monotherapy treatment, adjusted for sex, age, baseline-BP, dose and baseline antihypertensive use. All the analyses performed for SBP-GRS, DBP-GRS, PP-GRS were adjusted for the top 10 genetic principal components (PCs) of ancestry. Results: All three BP-GRS were significantly associated with RHTN (3,103 cases vs 3,163 controls): p=6.73 × 10-15 for SBP-GRS; p=2.86 × 10-4 for DBP-GRS; and p<10-16 for PP-GRS, with increased genetic risk of hypertension increasing odds of RHTN. Patients in the top 20% of SBP-GRS distribution had 1.78 × odds of RHTN compared with the lowest 20% (p=6.90 × 10-11).BP-GRS were also significantly associated with BP response to CCBs (n=1,780): eg, patients in the lowest 20% genetic risk group achieved better lowering response with a 3.79 mmHg mean difference between SBP pre and post treatment (p=4.9 × 10-4). However, results were non-significant for BB drug response. Conclusion: Our results confirm genetic contributions to both RHTN and BP drug response. Results indicate that RHTN patients are likely to be those with highest genetic risk of hypertension, hence the greater clinical challenge. These findings could aid the management of patients with RHTN in clinical practice, since genetic risk profiling could identify earlier those at risk.Similarly, we show that patients with greater BP genetic risk respond less effectively to antihypertensive treatment, with less reduction of BP post-treatment. |
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| ISSN: | 1470-2118 |