Proteomic, metabolomic, and microbiome studies of blood pressure

Abstract: Hypertension is a major risk factor for cardiovascular disease and premature death with a substantial global economic burden. To prevent and treat hypertension, it is crucial to improve our understanding of the pathophysiological mechanisms. Hypertension is a multifactorial condition influenced both by genetic and environmental factors. Detailed measurement of the molecular composition in plasma (“omics”) and the gut microbiota can enable novel biological understanding. The overall aim of this thesis was to investigate the associations of proteins, metabolites, and gut microbiome composition with blood pressure and blood pressure changes over time.Study I investigated the associations of 79 proteins with 5-year blood pressure progression using a proximity extension assay. Only renin was significantly associated with blood pressure stage progression in discovery cohort. In the replication cohort, the association was attenuated and not statistically significant. However, in all three cohorts combined, higher baseline renin was associated with higher blood pressure at follow-up.Study II investigated the longitudinal associations of 220 metabolites with 5-year blood pressure progression using gas chromatography mass spectrometry and liquid chromatography-tandem mass spectrometry. Levels of ceramide (d18:1,C24:0), triacylglycerol (C16:0,C16:1), total glycerolipids, and oleic acid (C18:cis[9]1) were positively associated, and cholesterylester C16:0 was negatively associated, with diastolic blood pressure change in the discovery cohort. Of the five top findings in the discovery cohort, two had related metabolites with a similar chemical structure that were also associated with diastolic blood pressure change over time in an independent cohort (the glycerolipids diacylglycerol (36:2) and monoacyl-glycerol (18:0)).Study III investigated the prevalence, variability, and reproducibility of blood pressure phenotypes based on office and 24-hour ambulatory measurements in SCAPIS (Swedish CArdioPulmonary BioImage Study), a large community-based cohort. The total sample size was 5881 participants (3026 women), with a mean office blood pressure of 125/77 mmHg and mean 24-hour ambulatory blood pressures of 124/76 mmHg. Approximately one-third of the participants had evidence of white-coat hypertension, similar to the proportion that had evidence of masked hypertension.Study IV investigated the associations between gut microbiota species and 24-hour ambulatory blood pressure in the SCAPIS study. We found robust evidence of a positive association of Dorea longicatena, and a negative association of Alistipes sp. 6CPBBH3, with the 24-h mean systolic blood pressure and diastolic blood pressure.This thesis demonstrated the utility of high-throughput omics technologies to identify proteins, metabolites and gut microbiota species associated with blood pressure phenotypes, and highlights the large problem of uncontrolled hypertension.