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Title: Blood pressure-lowering agents response : a systematic review and genome wide study
Author: Alsanosi, Safaa Mohammed M.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2017
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In spite of the vast amount of evidence on the benefits of blood pressure (BP) lowering that has accumulated to date, hypertension (HTN) remains the leading risk factor for disease and disability worldwide. Since the first BP-lowering agents became available in the 1950s, their effects have been tested thoroughly by means of the best evidence-providing approach, namely, large randomised controlled trials (RCTs). In the same way, the pharmacogenomics of HTN have the potential to identify genetic biomarkers that predict the response of BP-lowering agents through genome-wide association studies (GWAS), which analyse quantitative traits at millions of markers across the genome to identify genetic variations that could contribute to HTN. For the most part, computational approaches and software tools have played a significant role in translating RCTs and GWAS findings. This thesis aims first to systematically review the BP responses of main BP-lowering agents, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics (DIs) and beta-blockers (BBs) in RCTs, and second to identify the single nucleotide polymorphisms (SNPs) associated with the BP-lowering responses of CCBs and BBs on Nordic Diltiazem (NORDIL) subjects using GWAS. Description of the research results: Following the Population Intervention Comparison Outcome Study (PICOS) design framework, a literature search of multiple sources resulted in the identification of 10,577 publications, with 5,568 unique records identified after duplicates were excluded. In total, 184 studies were identified as potentially eligible, of which 82 RCTs with a total of 197,684 participants were selected for quantitative synthesis. With regard to BP-lowering strategies, 13 studies with 41,886 participants focused on lowering BP intentionally, while the remaining 69 studies (155,798 participants) were classified as unintentional BP-lowering studies. Risk of bias in included studies: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, all included studies were described as RCTs; however, most studies did not address how treatment randomization occurred or how allocation of treatment was concealed. All included studies also stated that they were double-blind studies, but again, most did not describe how the double blinding was ensured throughout the studies. The risk of attrition bias was avoided as all randomized participants were included in the analysis. All of the studies had a low risk for reporting bias. BP-lowering agents were added to randomly allocated treatment to control high BP; consequently, one potentially unclear source of bias was present in 13 of the 82 studies. The overall quality was rated to be acceptable to high. In all, 48 studies were rated to be high-quality studies, and 34 studies were rated as acceptable quality. Effect of intervention: After a systematic search and selection process, 56 studies were included in the analysis of delta BP response, 37 studies were included in the analysis of single-measure BP response and 20 studies were included in the analysis of repeated measures. A number of BP-lowering agents showed a significantly (P<0.05) superior BP response in comparison with other agents included in the review; however, the level of BP response was still small. CCBs were superior to ACEIs in lowering both systolic BP (SBP) and diastolic BP (DBP). DIs were superior to ACEIs and CCBs in lowering SBP. ARBs were superior to BBs in lowering SBP. CCBs and DIs were significantly superior to placebos in lowering both SBP and DBP. Genome-wide study: Following NORDIL quality control standards, a final set of 3,850 samples and 500,905 SNPs was available for analysis. In total, 51 SNPs showed a significant (P<1X10-5) association with BP response. The top discordant signals identified in NORDIL included five SNPs for SBP on BB arm, seven SNPs for DBP on BB arm, 12 SNPs for SBP on CCB arm and nine SNPs for DBP on CCB arm. Discordant SNPs from the NORDIL were replicated, based on the interests of five collaborative RCTs; including 11 SNPs for SBP on BB arm, 22 SNPs for DBP on BB arm, 23 SNPs for SBP on CCB arm and 18 SNPs for DBP on CCB arm. However, no SNP achieved a genome-wide significance of (P<5x10-8). Future recommendations: Further systematic reviews of RCTs comparing different BP-lowering agents are required to provide evidence of the options for BP-lowering medication. Specifically, there is a need to study BP response as an outcome by itself, taking into account different BP-lowering agent combinations,including classes and sub-classes, along with co-morbidities such as type 2 diabetes mellitus, coronary heart disease and chronic renal failure. Regarding the genome-wide study, further studies are needed to clarify the potential contribution of plausible SNPs in relation to CCB and BB response in HTN. These studies should include comprehensive sequencing of the candidate interval, genotyping of variants in many population samples, testing for association, functional studies and investigation of interactions with other genes or environmental factors. Furthermore, genome-wide studies need to identify directionally discordant signals between SNP and BP response for BB and CCB and confirm the validity of a SNP BP response by analysing the SNP effect on mortality.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General) ; RM Therapeutics. Pharmacology