Genetic Determinants Of Hypertension Research Articles

Genetic determinants of hypertension in two national cohorts of Mountain Shoria

To estimate the prevalence of the genotypes of the candidate genes ACE (I/D, rs4646994), ADRB1 (Ser49Gly, A/G, rs1801252) ADRA2B (I/D), MTHFR (C677T, Ala222Val, rs1801133), and eNOS (4b/4a) and their association with hypertension in two ethnic groups of Mountain Shoria. A clinical and epidemiological study was conducted in a population compactly living in the hard-to-reach areas of Mountain Shoria (the settlements of Orton, Ust-Kabyrza, and Sheregesh of the Kemerovo Region). A continuous method was used to survey 1178 residents from the above settlements; the sample consisted of adults (aged 18 years and older), 565 people were genotyped. The prevalence of hypertension among the population of Mountain Shoria was 42.3%. The incidence of this disease among the Shorians was lower (39.9%) than that among the representatives of non-indigenous people (46.1%). The ethnically justified peculiarities of the association of ADRA2B and ACE I/D polymorphisms with hypertension were established. There were fewer patients with hypertension among ACE ID and ADRA2B DD genotype carriers in the cohort of the Shorians than in that of the non-indigenous population: 40.6% versus 58.6% and 38.3% versus 64%, respectively. Conversely, there were more hypertensive patients among the carriers of the homozygous ACE DD genotype in the native ethnic group (60%) than in the non-indigenous one (37.1%). Adverse prognostic ACE DD, ADRB1 AA, MTHFR TT, and eNOS 4a/4a genotypes were more frequently observed in the non-indigenous ethnic groups; the ADRA2B DD genotype was more common in the native population. Hypertension was associated with the ACE DD, МTHFR CT, and ADRB1 AA genotypes in the native ethnic group and with the ACE ID genotype in the non-indigenous population.

The Epithelial Na+ Channel as a Determinant of Blood Pressure

The epithelial Na+ channel (ENaC) forms the rate limiting step in transepithelial Na+ absorption across aldosterone- responsive tissues such as the distal nephron. After more than a decade of investigation it is clear that the mechanisms of ENaC regulation are complex with an array of ENaC-regulatory proteins having been identified. A variety of monogenic syndromes of low renin hypertension have been identified that serve, through different mechanisms, to upregulate distal tubular ENaC activity. One of the most extensively studied, Liddles syndrome, results predominantly from mutations in the C-termini of β and γ-ENaC subunits leading to a failure of Nedd4-2 (neuronal precursor cell-expressed and developmentally down-regulated protein 4-2) mediated channel endocytosis and an increased expression of ENaC at the cell surface. The role of ENaC subunit polymorphisms as determinants of essential hypertension has been investigated in a number of studies. The T594M mutation in the β-subunit of ENaC, for example, has been screened in large study populations and there is conflicting evidence that it co-segregates with blood pressure. Reasons for such controversies are discussed. The authors conclude that ENaC is a pivotal convergence point in blood pressure regulation and that future studies must identify better ways to measure distal tubular ENaC activity and investigate the importance of combination polymorphisms of ENaC subunits and their regulatory proteins as genetic determinants of hypertension.

The impact of molecular medicine upon early cardiovascular drug development.

Heart disease remains the leading cause of death and morbidity in the western world despite significant advances in cardiovascular (CVS) therapeutics. Since the 1960s clinical pharmacologists have been very much involved in bringing forward new classes of CVS drugs. This started with the introduction of β-adrenoceptor blockers in the early 1960s and has continued with calcium antagonists, ACE inhibitors and more recently endothelin antagonists. The principles for classical drug design have been based upon interaction with: receptor sites (β-adreno-ceptor blockers), enzymes (thrombolytics and anticoagulants) and ion channels (calcium antagonists, antiarrhythmics). The advent of molecular biology has added a fourth principle for CVS drug development – that of molecular therapeutics. While classical approaches will still provide new CVS drugs (e.g. platelet IIb/IIIa receptor antagonists and directly acting thrombin inhibitors), there is now anticipation that molecular therapeutics will provide a very specific means of intervention thus potentially avoiding some of the problems associated with the non specificity of conventional approaches, e.g. side-effects associated with lack of cardioselectivity with β-adrenoceptor blockers, risk of bleeding with anticoagulants, cough with ACE inhibitors, controversy following retrospective analysis of the use of calcium antagonists. In the broader sense molecular therapeutics includes both gene therapy and oligonucleotide therapy. However the advances in genetic analysis (identification of polymorphisms associated with diseases) mean that there may be a further impact upon drug development – namely the use of known gene polymorphisms to select patient populations at risk. We will review the status of each of these and prospects for the future.

Genetics '96 Satellite Symposim of the ISH, June 21, 1996, Glasgow, Scotland

The molecular genetics of hypertension has been an exciting and fruitful field of scientific discovery over recent years. This Genetics Symposium was held in Glasgow earlier this year (June 21) as a satellite of the International Society of Hypertension. It brought together scientists and clinicians dedicated to developing a clearer insight into the genetic determinants of hypertension, both in experimental models and in human essential hypertension. The first of these articles follow, and the remainder will appear in next month's journal. In the first session of the symposium, concepts and strategies were discussed by Drs Klaus Lindpaintner, Nicholas Schork, Florent Soubrier, and Howard Jacob. It has become clear that new approaches for dissection of complex polygenic disorders such as hypertension require the development of a new statistical genetic strategy. Dr Schork discussed extensions to the standard quantitative trait loci (QTL mapping approach), which included accommodation of heterogeneity, modeling of multiple-loci …

Identifying the genetic determinants of hypertension.

Identifying the genetic determinants of hypertension.