GRK4基因rs1801058多态位点与新诊断高血压患者急性盐负荷试验血压反应的关联研究

doi:10.5246/jcps.2025.01.006

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (1): 66-74.DOI: 10.5246/jcps.2025.01.006

• 【药事管理与临床药学专栏】 • 上一篇下一篇

GRK4基因rs1801058多态位点与新诊断高血压患者急性盐负荷试验血压反应的关联研究

王雪¹^,^#, 王鸿懿²^,^#, 张昕怡¹, 田彦³, 杨莉⁴, 韩晓霞⁵, 王卓³, 聂小燕¹, 孙宁玲²^,^*()

^1. 北京大学药学院药事管理与临床药学系, 北京 100191
^2. 北京大学人民医院高血压科, 北京 100044
^3. 北京益序医疗科技有限公司, 北京 100192
^4. 昆明医科大学附属延安医院, 云南昆明 650500
^5. 清徐县人民医院, 山西太原 030400

收稿日期:2024-08-21 修回日期:2024-09-20 接受日期:2024-10-15 出版日期:2025-02-20 发布日期:2025-02-20
通讯作者: 孙宁玲

GRK4 gene rs1801058 polymorphism and blood pressure response to acute salt loading test in newly diagnosed hypertension patients

Xue Wang¹^,^#, Hongyi Wang²^,^#, Xinyi Zhang¹, Yan Tian³, Li Yang⁴, Xiaoxia Han⁵, Zhuo Wang³, Xiaoyan Nie¹, Ningling Sun²^,^*()

¹ Department of Pharmacy Administration and Clinical Pharmacy School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
² Department of Hypertension, People's Hospital, Peking University, Beijing 100044, China
³ Beijing E-Seq Medical Technology Co. Ltd., Beijing 100192, China
⁴ Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650500, Yunnan, China
⁵ Qingxu County People's Hospital, Taiyuan 030400, Shanxi, China

Received:2024-08-21 Revised:2024-09-20 Accepted:2024-10-15 Online:2025-02-20 Published:2025-02-20
Contact: Ningling Sun
About author:
^# Xue Wang and Hongyi Wang have contributed equally and are co-first authors.

摘要/Abstract

摘要：

肾脏多巴胺D1受体功能够促进肾脏尿钠排泄, 而G蛋白偶联受体激酶4 (GRK4)对肾脏多巴胺D1受体的功能起着重要作用, 既往研究显示GRK4基因多态位点与高血压盐敏感性相关, 其中rs1801058 T等位基因在东亚人群中约有50%的频率, 但缺乏与盐敏感性相关的功能证据。本研究通过对高血压患者进行rs1801058基因测序, 探索该位点多态性与患者急性盐负荷的血压反应的关联, 从而进一步找到该位点与盐敏感性的关系。研究的数据表明, rs1801058基因型与盐负荷后的血压变化没有统计学显著差异, 但携带C等位基因的患者表现出显著的心率增快; 而利尿缩容后, 在≤40岁的亚组患者中, T等位基因携带者的收缩压、舒张压、平均动脉压和心率的变化均高于C等位基因携带者。研究表明GRK4单个rs1801058多态性不能直接解释中国高血压患者的盐敏感性。

关键词: GRK4, rs1801058, 盐敏感性, 高血压

Abstract:

G-protein coupled receptor kinase 4 (GRK4) gene plays a core role in renal dopamine D1 receptor function for handing renal sodium excretion, the rs1801058 T variant has ~50% frequency in the general East Asian population but lacks functional evidence for salt-sensitivity. In this prospective study, we identified rs1801058 genotypes by sequencing in hypertensives patients and analyzed the variant’s effects on blood pressure response to acute salt loading in 150 newly diagnosed hypertension patients. Our data indicated that there were no statistically significant difference in blood pressure changes between the overall rs1801058 genotype groups. Carriers of the C allele showed a significant rise in heart rate change according to acute saline loading. Among patients age ≤ 40year, T allele carriers showed higher changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) than C allele carriers when diuretic shrinkage. GRK4 single rs1801058 polymorphism cannot directly explain salt sensitivity in the Chinese hypertension patients.

Key words: GRK4, rs1801058, Salt-sensitivity, Blood pressure response

Supporting:

王雪, 王鸿懿, 张昕怡, 田彦, 杨莉, 韩晓霞, 王卓, 聂小燕, 孙宁玲. GRK4基因rs1801058多态位点与新诊断高血压患者急性盐负荷试验血压反应的关联研究[J]. 中国药学(英文版), 2025, 34(1): 66-74.

Xue Wang, Hongyi Wang, Xinyi Zhang, Yan Tian, Li Yang, Xiaoxia Han, Zhuo Wang, Xiaoyan Nie, Ningling Sun. GRK4 gene rs1801058 polymorphism and blood pressure response to acute salt loading test in newly diagnosed hypertension patients[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(1): 66-74.

图/表 5

Table 1. Baseline characterisitics of studied participants.

Table 2. Blood Pressure change during the acute salt loading test by GRK4 Genotype.

Figure 1. Boxplots of outcomes with significant inter-group difference. Notes: X24h.UK means 24 h urinary sodium at the first day admission; Change 1. HR means the heart rate change according to acute saline loading test compared with the baseline level. Change 2. DBP means the diastolic blood pressure change according to furosemide shrinkage compared with the level when acute saline loading test finishing. X3hUK means the collection of 3-h urinary potassium when furosemide shrinkage.

Figure 2. Boxplots of BP and HR change after acute saline loading test sub-grouped by year. Notes: Group year < 40 including who were in 40 year. BP means blood pressure; HR means heart rate; Change 1. SBP/DBP/MAP/HR means the systolic blood pressure/diastolic blood pressure/mean arterial pressure/heart rate change according to acute saline loading test compared with the baseline level.

Figure 3. Boxplots of BP and HR change after diuretics shrinkage sub-grouped by year. Notes: Group year < 40 including who were in 40 year. BP means blood pressure; HR means heart rate; Change 2. SBP/DBP/MAP/HR means the systolic blood pressure/diastolic blood pressure/mean arterial pressure/heart rate change according to acute saline loading test compared with the baseline level.

参考文献 21

[1]	Roth, G.A.; Mensah, G.A.; Johnson, C.O.; Addolorato, G.; Ammirati, E.; Baddour, L.M.; Barengo, N.C.; Beaton, A.Z.; Benjamin, E.J. ; Benziger, C.P.; Bonny, A.; Brauer, M.; Brodmann, M.; Cahill, T.J.; Carapetis, J.; Catapano, A.L.; Chugh, S.S.; Cooper, L.T.; Coresh, J.; Criqui, M.; DeCleene, N.; Eagle, K.A.; Emmons-Bell, S.; Feigin, V.L.; Fernández-Solà, J.; Fowkes, G.; Gakidou, E.; Grundy, S.M.; He, F.J.; Howard, G.; Hu, F.; Inker, L.; Karthikeyan, G.; Kassebaum, N.; Koroshetz, W.; Lavie, C.; Lloyd-Jones, D.; Lu, H.S.; Mirijello, A.; Temesgen, A.M.; Mokdad, A.; Moran, A.E.; Muntner, P.; Narula, J.; Neal, B.; Ntsekhe, M.; Moraes de Oliveira, G.; Otto, C.; Owolabi, M.; Pratt, M.; Rajagopalan,S.; Reitsma, M.; Ribeiro, A.L.P.; Rigotti, N.; Rodgers, A.; Sable, C.; Shakil, S.; Sliwa-Hahnle, K.; Stark, B.; Sundström, J.; Timpel, P.; Tleyjeh, I.M.; Valgimigli, M.; Vos, T.; Whelton, P.K.; Yacoub, M.; Zuhlke, L.; Murray, C.; Fuster, V.; Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J. Am. Coll. Cardiol. 2020, 7, 2982–3021.
[2]	World health statistics 2024: monitoring health for the SDGs, Sustainable Development Goals. Geneva: World Health Organization. 2024. Licence: CC BY-NC-SA 3.0 IGO.
[3]	Global report on hypertension: the race against a silent killer. Geneva: World Health Organization. 2023. Licence: CC BY-NC-SA 3.0 IGO.
[4]	He, J.; Gu, D.; Chen, J.; Jaquish, C.; Rao, D.; Hixson, J.; Chen, J.C.; Duan, X.; Huang, J.F.; Chen, C.S.; Kelly, T.; Bazzano, L.; Whelton, P. Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study. J. Hypertens. 2009, 27, 48–54.
[5]	Afolabi, J.; Laffer, C.L.; Beasley, H.K.; Hinton, A.; Masenga, S.K.; Kirabo, A. Salt Sensitivity of Blood Pressure. Circ. Res. 2024, 13, 1234–1239.
[6]	Kawasaki, T.; Delea, C.S.; Bartter, F.C.; Smith, H. The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension, Am. J. Med. 1978, 64, 193–198.
[7]	Kurtz, T.W.; DiCarlo, S.E.; Pravenec, M.; Morris, R.C.Jr. The American Heart Association Scientific Statement on salt sensitivity of blood pressure: Prompting consideration of alternative conceptual frameworks for the pathogenesis of salt sensitivity? J. Hyper. 2017, 35, 2214–2225.
[8]	Beheray, S.; Kansra,V.; Hussain, T.; Lokhandwala, M.F. Diminished natriuretic response to dopamine in old rats is due to an impaired D1-like receptor-signaling pathway. Kidney Int. 2000, 58, 712–720.
[9]	Sanada, H.; Yatabe, J.; Midorikawa, S.; Hashimoto, S.; Watanabe, T.; Moore, J.H.; Ritchie, M.D.; Williams, S.M.; Pezzullo, J.C.; Sasaki, M.; Eisner, G.M.; Jose, P.A.; Felder, R.A. Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. Clin. Chem. 2006, 52, 352–360.
[10]	Jose, P.A.; Eisner, G.M.; Felder, R.A. Role of dopamine receptors in the kidney in the regulation of blood pressure. Curr. Opin. Nephrol. Hypert. 2002, 11, 8–92.
[11]	Byrd, J.B. Personalized medicine and treatment approaches in hypertension: current perspectives. Integr. Blood Press. Contr. 2016, 59.
[12]	Vandell, A.G.; Lobmeyer, M.T.; Gawronski, B.E.; Langaee, T.Y.; Gong, Y.; Gums, J.G.; Beitelshees, A.L.; Turner, S.T.; Chapman, A.B.; Cooper-DeHoff, R.M.; Bailey, K.R.; Boerwinkle, E.; Pepine, C.J.; Liggett, S.B.; Johnson, J.A. G protein receptor kinase 4 polymorphisms: β-blocker pharmacogenetics and treatment-related outcomes in hypertension. Hypertension. 2012, 60, 957–964.
[13]	Hussain, T.; Lokhandwala, M.F. Renal dopamine DA1 receptor coupling with G(S) and G(q/11) proteins in spontaneously hypertensive rats. Am. J. Physiol. 1997, 272, F339–346.
[14]	Yang, J.; Hall, J.E.; Jose, P.A.; Chen, K.; Zeng, C.Y. Comprehensive insights in GRK4 and hypertension: From mechanisms to potential therapeutics. Pharmacol. Ther. 2022, 239, 108194.
[15]	Premont, R.T.; MacRae, A.D.; Stoffel, R.H.; Chung, N.; Pitcher, J.A.; Ambrose, C.; Inglese, J.; MacDonald, M.E.; Lefkowitz, R.J. Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants. J. Biol. Chem. 1996, 271, 6403–6410.
[16]	N.C.f.B.I. (NCBI), "Single Nucleotide Polymorphism (SNP) rs1801058.", NCBI dbSNP Database. This data can be found online at https://www.ncbi.nlm.nih.gov/snp/rs1801058#frequency_tab.
[17]	Jiang, W.; Wang, X.; Li, R.P.; Wang, G. Shan, J.X.; Gu, M. Targeted capture sequencing identifies genetic variations of GRK4 and RDH8 in Han Chinese with essential hypertension in Xinjiang. PloS One. 2021, 16, e0255311.
[18]	Zhang, H.; Sun, Z.Q.; Liu, S.S.; Yang, L.N. Association between GRK4 and DRD1 gene polymorphisms and hypertension: a meta-analysis. Clin. Int. Aging. 2016, 11, 17–27.
[19]	Liu, C.; Xi, B. Pooled analyses of the associations of polymorphisms in the GRK4 and EMILIN1 genes with hypertension risk. Int. J. Med. Sci. 2012, 9, 274–279.
[20]	Weinberger, M.H.; Miller, J.Z.; Luft, F.C.; Grim, C.E.; Fineberg, N.S. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986, 8, Ii127–134.
[21]	Muskalla, A.M.; Suter, P.M.; Saur, M.; Nowak, A.; Hersberger, M.; Krayenbuehl,P.-A. G-Protein Receptor Kinase 4 Polymorphism and Response to Antihypertensive Therapy. Clin. Chem. 2014, 60, 1543–1548.

GRK4基因rs1801058多态位点与新诊断高血压患者急性盐负荷试验血压反应的关联研究

GRK4 gene rs1801058 polymorphism and blood pressure response to acute salt loading test in newly diagnosed hypertension patients

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 5

参考文献 21

相关文章 6

编辑推荐

Metrics

本文评价

[1]	张晓明, 朱世慧, 高艺文, 李建橡, 张楠, 岳桂华. 黄连解毒汤对自发性高血压大鼠心脏内质网应激的影响[J]. 中国药学(英文版), 2024, 33(7): 609-619.
[2]	孙娜, 王谕靖, 周彩红, 亢欢欢, 马烁, 张玉, 袁宇涵, 张新, 靳琳萱, 李文倩, 吴欣茹, 舒朋华. 基于综合网络药理策略研究夏枯草降压作用机制[J]. 中国药学(英文版), 2024, 33(11): 1068-1081.
[3]	张楠, 高艺文, 吕婵梅, 杨晓丽, 岳桂华. 黄连解毒汤对自发性高血压大鼠血管内皮因子及RhoA蛋白表达的影响[J]. 中国药学(英文版), 2019, 28(2): 114-120.
[4]	郑凯, 孙迎琪, 魏艳红, 杨巍, 孔维华, 邵宏^*, 王天晟. 北京三家综合医院抗高血压用药方案组成及主要治疗患者分析[J]. , 2013, 22(4): 370-376.
[5]	朱孔彩, 曹国颖^*, 胡欣. 血液透析患者的高血压药物控制[J]. , 2012, 21(3): 205-210.
[6]	魏巍, 傅继华^, 苏长海, 单英, 王渊, 孔树佳, 赵继会, 吕万良^^*, 王树明, 王丽 . 复方比索洛尔硝酸异山梨酯透皮贴剂自发性高血压大鼠的心血管保护作用[J]. , 2008, 17(3): 241-248.