Molecular Mechanisms of Human Hypertension

Association studies with candidate genes have been widely used for the study of complex diseases. However, this approach has been criticized because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms. These challenges have led to pessimism about the candidate-gene approach and about the genetic analysis of complex diseases in general. We believe that these criticisms can be usefully countered with an appeal to the principles of epidemiological investigation.

Candidate-gene approaches for studying complex genetic traits: practical considerations.

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.

https://pharmrev.aspetjournals.org/content/pharmrev/57/1/27.full.pdf

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.

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Sex-specific genetic architecture of human disease

A population-based study of a quantitative trait may be seriously compromised when the trait is subject to the effects of a treatment. For example, in a typical study of quantitative blood pressure (BP) 15 per cent or more of middle-aged subjects may take antihypertensive treatment. Without appropriate correction, this can lead to substantial shrinkage in the estimated effect of aetiological determinants of scientific interest and a marked reduction in statistical power. Correction relies upon imputation, in treated subjects, of the underlying BP from the observed BP having invoked one or more assumptions about the bioclinical setting. There is a range of different assumptions that may be made, and a number of different analytical models that may be used. In this paper, we motivate an approach based on a censored normal regression model and compare it with a range of other methods that are currently used or advocated. We compare these methods in simulated data sets and assess the estimation bias and the loss of power that ensue when treatment effects are not appropriately addressed. We also apply the same methods to real data and demonstrate a pattern of behaviour that is consistent with that in the simulation studies. Although all approaches to analysis are necessarily approximations, we conclude that two of the adjustment methods appear to perform well across a range of realistic settings. These are: (1) the addition of a sensible constant to the observed BP in treated subjects; and (2) the censored normal regression model. A third, non-parametric, method based on averaging ordered residuals may also be advocated in some settings. On the other hand, three approaches that are used relatively commonly are fundamentally flawed and should not be used at all. These are: (i) ignoring the problem altogether and analysing observed BP in treated subjects as if it was underlying BP; (ii) fitting a conventional regression model with treatment as a binary covariate; and (iii) excluding treated subjects from the analysis. Given that the more effective methods are straightforward to implement, there is no argument for undertaking a flawed analysis that wastes power and results in excessive bias.

Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure.

Background—There is controversy regarding the association of the angiotensin-converting enzyme deletion-insertion (ACE D/I) polymorphism with systemic hypertension and with blood pressure. We investigated these relations in a large population-based sample of men and women by using association and linkage analyses. Methods and Results—The study sample consisted of 3095 participants in the Framingham Heart Study. Blood pressure measurements were obtained at regular examinations. The ACE D/I polymorphism was identified by using a polymerase chain reaction assay. In logistic regression analysis, the adjusted odds ratios for hypertension among men for the DD and DI genotypes were 1.59 (95% confidence interval [CI], 1.13 to 2.23) and 1.18 (95% CI, 0.87 to 1.62), respectively, versus II (χ2 P=.02). In women, adjusted odds ratios for the DD and DI genotypes were 1.00 (95% CI, 0.70 to 1.44) and 0.78 (95% CI, 0.56 to 1.09), respectively (P=.14). In linear regression analysis, there was an association of the ACE DD ...

Evidence for Association and Genetic Linkage of the Angiotensin-Converting Enzyme Locus With Hypertension and Blood Pressure in Men but Not Women in the Framingham Heart Study

The platelet glycoprotein IIb/IIIa (GP IIb/IIIa) plays a pivotal role in platelet aggregation Recent data suggest that the Pl A2 polymorphism of GPIIIa may be associated with an increased risk for cardiovascular disease However, it is unknown if there is any association between this polymorphism and platelet reactivity We determined GPIIIa genotype and platelet reactivity phenotype data in 1422 subjects from the Framingham Offspring Study Genotyping was performed using PCR based restriction fragment length polymorphism analysis Platelet aggregability was evaluated by the Born method The threshold concentrations of epinephrine and adenosine diphosphate (ADP) were determined Allele frequencies of Pl A1 and Pl A2 were 084 and 016, respectively The presence of one or two Pl A2 alleles was associated with increased platelet aggregability as indicated by incremen- tally lower threshold concentrations for epinephrine and ADP For epinephrine, the mean concentrations were 09 µmol/L (09–10) for homozygous Pl A1 , 07 µmol/L (07–09) for the heterozygous Pl A1 / Pl A2 and 06 µmol/L (04–10) for homozygous Pl A2 individuals, p = 0009 The increase in aggregability induced by epinephrine remained highly significant (p = 0007) after adjustment for covariates For ADP-induced aggregation, the respective mean concentrations were 31 µmol/L (30–32), 30 µmol/L (29–32), and 28 µmol/L (24–33), p = 019 after adjustment for covariates Our findings indicate that molecular variants of the gene encoding GPIIIa play a role in platelet reactivity in vitro Our observations are compatible with and provide an explanation for the reported association of the Pl A2 allotype with increased risk for cardiovascular disease

Increased Platelet Aggregability Associated With Platelet GPIIIa PlA2 Polymorphism : The Framingham Offspring Study

—Unexplained, persistent cough limits the use of angiotensin-converting enzyme (ACE) inhibitors in a significant number of patients. It has been speculated that occurrence of this adverse effect is genetically predetermined; in particular, variants of the genes encoding ACE, chymase, and B2-bradykinin receptor have been implicated. To investigate this question, we determined genotypes for common polymorphisms for these three genes in subjects with a history of ACE inhibitor–related cough. Specificity of the adverse effect was confirmed by a blinded, double-crossover design protocol in which subjects were rechallenged with either lisinopril or placebo. In 99 case subjects and 70 control subjects (who failed to develop cough on rechallenge with ACE inhibitor) thus selected, frequencies for the ACE D and I alleles were 0.56 and 0.44 (cases) and 0.56 and 0.44 (controls), respectively; frequencies for chymase A and B alleles (absence/presence of Bst XI site) were 0.56 and 0.44 (cases) and 0.46 and 0.54 (controls), respectively; frequencies for B2-bradykinin receptor + and − alleles (presence/absence of a 21 to 29 nonanucleotide sequence) were 0.52 and 0.48 (cases) and 0.53 and 0.47 (controls), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for association between genotype at either gene examined and cough (adjusted for gender and age). Our data indicate that common genetic variants of ACE, chymase, and B2-bradykinin receptor do not explain the occurrence of ACE inhibitor–related cough.

Valluri S. Rao

Papers

Evidence for Association and Genetic Linkage of the Angiotensin-Converting Enzyme Locus With Hypertension and Blood Pressure in Men but Not Women in the Framingham Heart Study

Increased Platelet Aggregability Associated With Platelet GPIIIa PlA2 Polymorphism : The Framingham Offspring Study

Three Candidate Genes and Angiotensin-Converting Enzyme Inhibitor–Related Cough: A Pharmacogenetic Analysis