Genetic variants of GRK4 influence circadian rhythm of blood pressure and response to candesartan in hypertensive patients

Q: What are the key findings of this study?

GRK4 genetic variants increased the likelihood of a non-dipper BP pattern (OR 6.672, 95% CI 5.124–8.688) and yielded a greater 24 h mSBP drop with candesartan (21.21 vs 12.34 mmHg, P<.001).

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Untreated essential hypertension (n=1239). Intervention: GRK4 genetic variants (A142V, A486V, R65L) in patients treated with candesartan vs. GRK4 wild-type (GRK4-WT) in patients treated with candesartan 4 mg/day. Primary outcome: Non-dipper blood pressure circadian rhythm and 24-hour mean systolic blood pressure reduction after 4-week candesartan treatment (OR 6.672, 95% CI 5.124-8.688, p=<0.001).

Q: What does this research mean for the field?

Hypertensive patients with GRK4 genetic variants are significantly more likely to have a non-dipper blood pressure pattern and exhibit a greater antihypertensive response to candesartan. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To examine the relationship between GRK4 genetic variants and circadian blood pressure rhythm, and to determine their effect on the antihypertensive efficacy of candesartan.

Nian Cao; Hui Tang; Miao Tian; Xue Gong; Zaicheng Xu; Binqing Zhou; Cong Lan; Caiyu Chen; Shuang Qu; Shuo Zheng; Hongmei Ren; Chao Fan; Pedro A. José; Chunyu Zeng; Tianyang Xia

doi:10.1080/10641963.2021.1919357

April 25, 2021Clinical and Experimental HypertensionOpen Access

Genetic variants of GRK4 influence circadian rhythm of blood pressure and response to candesartan in hypertensive patients

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Key result

GRK4 variants linked to ~6.7-fold higher odds of non-dipper hypertension.

OR 6.672
95% CI 5.124-8.688
P<0.001
n=1,239

Why the study?

Little is known about the role of GRK4 variants in determining the circadian rhythm of blood pressure and response to candesartan in hypertension.

Do GRK4 genetic variants influence the circadian rhythm of blood pressure and the antihypertensive response to candesartan in untreated Han Chinese patients with hypertension?

Key Points

To examine the relationship between GRK4 genetic variants and circadian blood pressure rhythm, and to determine their effect on the antihypertensive efficacy of candesartan.
Conducted exon sequencing of GRK4 (identifying A142V, A486V, and R65L variants) in 1239 hypertensive patients.
Performed 24-hour ambulatory blood pressure monitoring before and after 4 weeks of candesartan therapy to evaluate diurnal variation and blood pressure reduction.
Patients with GRK4 variants were significantly more likely to display a non-dipping circadian rhythm than those with GRK4 wild type (OR 6.672, 95% CI 5.124–8.688, P < .001).
After 4 weeks of candesartan, patients with GRK4 variants showed a significantly greater drop in 24-hour mean systolic blood pressure compared to wild-type patients (21.21 ± 4.99 vs 12.34 ± 4.78 mmHg, P < .001).
Patients carrying GRK4 variants achieved greater reductions in morning peak systolic blood pressure (16.54 ± 4.37 vs 11.52 ± 4.14 mmHg, P < .001) and greater increases in smoothness index (1.44 ± .16 vs 1.17 ± .11, P < .001).

Study Design

Type

Cohort (n=1,239)

Multicenter

No

Structured PICO

Do GRK4 genetic variants influence the circadian rhythm of blood pressure and the antihypertensive response to candesartan in untreated Han Chinese patients with hypertension?

P

Population

1,239 untreated Han Chinese patients aged 40–70 years with hypertension (BP >=140/90 mmHg), free of secondary hypertension or severe comorbidities, treated with candesartan 4 mg/day and followed for 4 weeks.

E

Exposure

Presence of GRK4 genetic variants (A142V, A486V, R65L; n=830) and treatment with oral candesartan 4 mg/day for 4 weeks

C

Comparator

GRK4 wild-type (GRK4-WT; n=409) receiving the same treatment of candesartan 4 mg/day for 4 weeks

O

Outcome

Association with non-dipper circadian rhythm of blood pressure (defined by diurnal variation rate of systolic blood pressure outside 10-20% drop on 24-hour ambulatory blood pressure monitoring) and antihypertensive response (drop in 24-hour mean systolic blood pressure [24 h mSBP]) at 4 weekssurrogate

Main Result

Odds Ratio: 6.672 (95% CI 5.124–8.688)

p-value: p=<0.001

Hypertensive patients carrying GRK4 genetic variants (A142V, A486V, R65L) have a markedly higher prevalence of non-dipper blood pressure patterns and achieve superior blood pressure reductions with candesartan compared to wild-type carriers.

Limitations

Exact mechanisms of how GRK4 variants influence blood pressure fluctuation require further investigation
Needs thorough assessment of the response of GRK4 variants to candesartan in a larger population
Mechanism by which GRK4 variants influence blood pressure fluctuation remains unclear and needs further investigation
Single-center study requiring validation in a larger population

Implication

GRK4 variants were associated with non-dipper BP and greater candesartan response; hypothesis-generating for genotype-guided therapy, requiring validation.

Abstract

Background: Genetic variants of coding genes related to blood pressure regulation participate in the pathogenesis of hypertension and determines the response to specific antihypertensive drugs. G protein-coupled receptor kinase 4 (GRK4) and its variants are of great importance in pathogenesis of hypertension. However, little is known about role of GRK4 variants in determine circadian rhythm of blood pressure and response to candesartan in hypertension. The aim of this study was to analyze the correlation of GRK4 variants and circadian rhythm of blood pressure, and to explore their effect on antihypertensive efficiency of candestartan.Methods: In this study, a total of 1239 cases were eligible, completed ambulatory blood pressure monitoring (ABPm) observation and exon sequencing of G protein-coupled receptor kinase 4 (GRK4). ABPm was obtained before and after 4-week treatment of candesartan. Diurnal variation of systolic blood pressure and antihypertensive effect of candesartan were then assessed.Results: Compared to GRK4 wild type (GRK4-WT), patients with GRK4 variants were more likely to be non-dippers (odds ratio (OR) 6.672, 95% confidence interval (CI) 5.124–8.688, P < .001), with GRK4 A142V (OR 5.888, 95% CI 4.332–8.003, P < .001), A486V (OR 7.102, 95% CI 5.334–9.455, P < .001) and GRK4 R65L (OR 3.273, 95% CI 2.271–4.718, P < .001), respectively. Correlation analysis revealed that non-dippers rhythm of blood pressure were associated with GRK4 variants (r = .420, P < .001), with GRK4 A142V (r = .416, P < .001), A486V (r = .465, P < .001) and GRK4 R65L (r = .266, P < .001), respectively. When given 4-week candesartan, patients with GRK4 variants showed better antihypertensive effect as to drop in blood pressure (24 h mSBP, 21.21 ± 4.99 vs 12.34 ± 4.78 mmHg, P < .001) and morning peak (MP-SBP, 16.54 ± 4.37 vs 11.52 ± 4.14 mmHg, P < .001), as well as greater increase in trough to peak ratio (SBP-T/P, .71 ± .07 vs .58 ± .07, P < .001) and smoothness index (SBP-SI, 1.44 ± .16 vs 1.17 ± .11, P < .001) than those with GRK4 WT.Conclusion: This study indicates that hypertensive patients with GRK4 variants are more likely to be non-dippers. What’s more, patients with GRK4 variants possess a significantly better antihypertensive response to candesartan than those with GRK4 WT.

Discussion

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Cite This Study

Cao et al. (2021) conducted a cohort in Untreated essential hypertension (n=1,239). GRK4 genetic variants (A142V, A486V, R65L) in patients treated with candesartan vs. GRK4 wild-type (GRK4-WT) in patients treated with candesartan 4 mg/day was evaluated on Non-dipper blood pressure circadian rhythm and 24-hour mean systolic blood pressure reduction after 4-week candesartan treatment (OR 6.672, 95% CI 5.124-8.688, p=<0.001). GRK4 genetic variants increased the likelihood of a non-dipper BP pattern (OR 6.672, 95% CI 5.124–8.688) and yielded a greater 24 h mSBP drop with candesartan (21.21 vs 12.34 mmHg, P<.001).

synapsesocial.com/papers/6a74c99c0b1b00a0ee091b46 https://doi.org/10.1080/10641963.2021.1919357

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Genetic variants of GRK4 influence circadian rhythm of blood pressure and response to candesartan in hypertensive patients

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Genetic variants of GRK4 influence circadian rhythm of blood pressure and response to candesartan in hypertensive patients

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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