Genetic predisposition to high blood pressure and out-of-office hypertension: insights from a population sample in Liechtenstein

Genetic predisposition is a risk factor for office hypertension. We tested whether genetic background could identify individuals with ambulatory daytime hypertension in a sample of white Europeans from Liechtenstein. We evaluated two measures of predisposition to hypertension: family history and polygenic risk scores (PRS). Our analytic sample contained 1444 participants aged 25 to 41. Of the participants, 12% had office hypertension, while 37% had out-of-office hypertension. The correlation between blood pressure PRS and family history of hypertension was low (R2 = 4.96×10−3), but both were strongly associated with ambulatory blood pressure (2.2 mmHg per 1 SD increase [95% CI: 1.6, 2.7] & 2.4 mmHg increase with positive family history [95% CI: 1.3, 3.4], respectively). The PRS provides incremental improvement in predicting ambulatory systolic blood pressure beyond a validated blood pressure prediction score (ΔAIC = - 33), whereas family history does not (ΔAIC = 1). However, the difference in performance between a baseline prediction algorithm for identifying ambulatory systolic daytime hypertension (positive likelihood ratio of 6.87 [95% CI: 5.56, 8.49]; negative likelihood ratio of 0.45 [95% CI: 0.39, 0.51]) and the same model with PRS integrated (positive likelihood ratio of 7.69 [95% CI: 6.18, 9.57]; negative likelihood ratio of 0.43 [95% CI: 0.37, 0.49]) was modest. In conclusion, in a white European sample from Liechtenstein, PRS and family history are distinct constructs that are associated with increased clinical and ambulatory blood pressure. Unlike family history, polygenic risk scores provide incremental information in the identification of individuals with ambulatory hypertension. However, these gains are modest and warrant further development to improve predictive utility at the point-of-care. ### Competing Interest Statement DC received consulting fees from Roche Diagnostics and Trimedics, and speaker fees from Servier and BMS/Pfizer, all outside of the current work. LR and MR are key shareholders of the Dr Risch Medical Laboratory. During the course of the project, PMS became a full time employee at Deep Genomics, however his role was limited to before he began employment and the results/project are not related to the work he conducts at Deep Genomics. ST holds a junior scholar award from the FRQS (Fonds de recherche du Quebec Sante). GP holds the Canada Research Chair in Genetic and Molecular Epidemiology and Cisco Systems Professorship in Integrated Health Biosystems. SN, MRC, KG, AL, SA have nothing to disclose. ### Clinical Protocols ### Funding Statement We thank those who enrolled in the GAPP study. We also thank the government of the Principality of Liechtenstein, the health ministers, and the Liechtenstein Office of Public Health for their support. Finally, our thanks are especially due to the Princely House of Liechtenstein, which gave decisive support that enabled the initiation of this project. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The local ethics committee (KEK, Zurich, Switzerland) approved the study protocol, and written informed consent was obtained from each participant. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are either publicly available, contained in the manuscript, or available upon reasonable request to the authors * AIC : Akaike information criterion BP : blood pressure FHx : family history GAPP : Genetic and Phenotypic Determinants of Blood Pressure and Other Cardiovascular Risk Factors GWAS : genome wide association study PROOF-BP : PRedicting Out of OFfice Blood Pressure PRS : polygenic risk score RMSE : root mean square error