Abstract
Genome-wide association scans are beginning to identify risk alleles for a number of complex diseases and traits. Essential hypertension looked as though it would be an exception to this trend after the Wellcome Trust Case Control Consortium data were published in 2007. However, more recent scans and meta-analyses have reversed the fortunes of essential hypertension. A number of loci have been identified, including a new antihypertensive drug target in the guise of the serine/threonine kinase SPAK. This kinase forms part of a novel kinase cascade that regulates the NCCT (Na+/Cl- co-transporter; SLC12A3) in the kidney and is defective in a rare Mendelian hypertension syndrome (Gordon's syndrome). Genome-wide scans are also being used to look for alleles to predict individual response to antihypertensive drugs and their risk of causing side-effects. The results of these are expected in the near future and may finally deliver the long-awaited goal of personalized drug therapy for hypertensive patients.
Highlights
The idea that blood pressure (BP) and hypertension are polygenic traits arose half a century ago from the famous debate between George Pickering and Robert Platt about the nature of the frequency distribution of BP [1].Many epidemiological studies have subsequently confirmed the heritability of BP; its inheritance is not Mendelian as Platt believed, but rather complex
Essential hypertension looked as though it would be an exception to this trend after the Wellcome Trust Case Control Consortium data were published in 2007
The Global BPgen consortium has recently reported the results of a genome-wide association study (GWAS) meta-analysis using 34,433 subjects, which is an order of magnitude larger than any of the single-cohort GWAS preceding it [20]
Summary
The idea that blood pressure (BP) and (by definition) hypertension are polygenic traits arose half a century ago from the famous debate between George Pickering and Robert Platt about the nature of the frequency distribution of BP [1]. The second GWAS to report a genome-wide significant hit used an Amish cohort and identified a novel candidate gene in the form of STK39, a serine/threonine kinase called SPAK (STE20/SPS1-related proline- and alanine-rich kinase) [18] This is an intriguing result for two reasons. The Global BPgen consortium has recently reported the results of a GWAS meta-analysis using 34,433 subjects, which is an order of magnitude larger than any of the single-cohort GWAS preceding it [20] They have identified no less than eight loci with obvious candidate genes and some of these hits (in the region of CYP17A1, CYP1A2 and FGF5) carry very high levels of significance (P < 10–20) . There have been some notable recent successes using the GWAS approach - for example, in predicting individual risk of myositis on statin therapy [39] or the risk of bradycardia when using beta-blockers [40]
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