Schools of Biomedical Sciences and Pharmacy (W.R.R., R.J.S., M.J.C.), The University of Newcastle, Callaghan, NSW, Australia.
Precision Medicine Research Program (W.R.R., M.J.C.), New Lambton, NSW, Australia.
Circulation. 2024 Mar 26;149(13):1019-1032. doi: 10.1161/CIRCULATIONAHA.123.065394. Epub 2023 Dec 22.
Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetics of BP could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels.
In this observational genetic study, we leveraged cross-sectional data from up to 296 475 genotyped individuals drawn from the UK Biobank cohort for whom BP and urinary electrolytes (sodium and potassium), biomarkers of sodium and potassium intake, were measured. Biologically directed genetic scores for BP were constructed specifically among pathways related to sodium and potassium biology (pharmagenic enrichment scores), as well as unannotated genome-wide scores (conventional polygenic scores). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on BP.
Genetic risk and urinary electrolytes both independently correlated with BP. However, urinary sodium was associated with a larger BP increase among individuals with higher genetic risk in sodium- and potassium-related pathways than in those with comparatively lower genetic risk. For example, each SD in urinary sodium was associated with a 1.47-mm Hg increase in systolic BP for those in the top 10% of the distribution of genetic risk in sodium and potassium transport pathways versus a 0.97-mm Hg systolic BP increase in the lowest 10% (=1.95×10). This interaction with urinary sodium remained when considering estimated glomerular filtration rate and indexing sodium to urinary creatinine. There was no strong evidence of an interaction between urinary sodium and a standard genome-wide polygenic score of BP.
The data suggest that genetic risk in sodium and potassium pathways could be used in a precision medicine model to direct interventions more specifically in the management of hypertension. Intervention studies are warranted.
高血压是主要不良心血管事件的关键风险因素，但在许多个体中仍难以治疗。饮食干预是降低血压（BP）的有效方法，但并非对所有个体都同样有效。BP 具有遗传性，遗传学可能是克服治疗反应异质性的有用工具。我们研究了 BP 的遗传学是否可用于识别可能从降低钠摄入量和提高钾水平中获益的高血压个体。
在这项观察性遗传研究中，我们利用来自英国生物库队列的多达 296475 名经基因分型个体的横断面数据，这些个体的 BP 和尿电解质（钠和钾）、钠和钾摄入量的生物标志物均经过测量。专门针对与钠和钾生物学相关的途径构建了针对 BP 的生物导向遗传评分（药物遗传学富集评分），以及未注释的全基因组评分（常规多基因评分）。然后，我们测试了尿电解质和这些遗传评分与 BP 之间是否存在基因-环境相互作用。
遗传风险和尿电解质均与 BP 独立相关。然而，尿钠与具有较高钠和钾相关途径遗传风险的个体中 BP 的升高更为相关，而与遗传风险相对较低的个体相比，BP 的升高更为相关。例如，在钠和钾转运途径中遗传风险最高的 10%个体中，尿钠每增加一个标准差，收缩压升高 1.47mmHg，而遗传风险最低的 10%个体中，收缩压升高 0.97mmHg（1.95×10）。当考虑到估计的肾小球滤过率并将钠与尿肌酐指数化时，这种与尿钠的相互作用仍然存在。尿钠与 BP 的标准全基因组多基因评分之间没有强烈的相互作用证据。
数据表明，钠和钾途径中的遗传风险可用于精准医学模型，更具体地指导高血压管理中的干预措施。需要进行干预研究。
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