Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Pharmacogenomics and Pharmacogenetics of Hypertension: Update and Perspectives—The Adducin Paradigm
Paolo Manunta and
Giuseppe Bianchi
Division of Nephrology, Dialysis and Hypertension, University "Vita-Salute" San Raffaele Hospital, Milan, Italy
Address correspondence to: Dr. Paolo Manunta, Division of Nephrology, Dialysis, and Hypertension, University "Vita-Salute" San Raffale, Via Olgettina 60, 20131 Milan, Italy. Phone: +39-0226433006; Fax: +39-0226432384; E-mail: manunta.paolo{at}hsr.it
There is a growing literature on the potential prospective useof genome information to enhance success in finding new medicines.An example of a prospective efficacy of pharmacogenetic andpharmacogenomics is the detection and impact of adducin polymorphismon hypertension. Adducin is a heterodimeric cytoskeleton protein,the three subunits of which are encoded by genes (ADD1, ADD2,and ADD3) that map to three different chromosomes. A long seriesof parallel studies in the Milan hypertensive rat strain modelof hypertension and humans indicated that an altered adducinfunction might cause hypertension through an enhanced constitutivetubular sodium reabsorption. In particular, six linkage studies,18 of 20 association studies, and four of five follow-up studiesthat measured organ damage in hypertensive patients supportthe clinical impact of adducing polymorphism. As many modulatorygenes and environment affect the adducin activity, the contextmust be taken into account to measure the clinical effect sizeof adducins. Pharmacogenomics is giving an important contributionto this end. In particular, the selective advantages of diureticsin preventing myocardial infarction and stroke over other antihypertensivetherapies that produce a similar BP reduction in carriers ofthe mutated adducin may support new strategies that aim to optimizethe use of antihypertensive agents for the prevention of hypertension-associatedorgan damage.
The enormous variation in the individual response to antihypertensivetreatment has led to acceleration of the interest in pharmacogenomicand pharmacogenetic studies with the consequent technologicaldevelopments (1). Publications on these fields have increasedsharply in the past 5 yr with the emergence of molecular geneticsand genotyping technologies in clinical investigations. Theterms pharmacogenomics and pharmacogenetics have been used interchangeablyin the literature; therefore, it is useful to define them here.Pharmacogenomics refers to the application of genome-wide approachesto understanding genetic influences on drug response and todeveloping novel drugs. It has the potential to uncover additiveor even synergistic influences of multiple genes on drug response.Historically, pharmacogenetic studies were developed initiallyto understand individual differences in drug pharmacokineticsand metabolism, often focused on single gene polymorphisms (SNP),especially in drug metabolism genes (1,2).
The Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure(3), the guideline for the management of hypertension of boththe European Society of Hypertension (4) and the British HypertensionSociety (5), delineates specific high-risk conditions that arecompelling indications for the use antihypertensive drug classesthat will be required to achieve goal BP (140/90 mmHg, or 130/80mmHg for patients with diabetes and chronic kidney disease).Moreover, lowering BP to the optimal goal levels seems to bemore important than specific drug selection. Indeed, the resultsof different meta-analyses (6,7) concluded that the treatmentwith any commonly used regimen (angiotensin-converting-enzymeinhibitors, calcium antagonists, angiotensin-receptor blockers,diuretics, and blockers) reduces the risk for total major cardiovascularevents, and larger reductions in BP produce larger reductionsin risk. Although the percentage of patients who had hypertensionand received treatment increased from 31 to 59% in the periodfrom 1976 to 1980 and to 70% in 2000, the percentage of patientswith high BP controlled to <140/90 mmHg is only approximately25% in Western industrialized countries, and this values hasbeen constant over the past 15 yr. Despite the great numberof antihypertensive drugs that are available the poor BP control,adverse effects represent approximately 80% of the causes forthe discontinuity of the antihypertensive therapy (8). Pharmacogenomicsmay reduce the interindividual variation to antihypertensivetherapy by tailoring therapy to individual genetic make-up.
However, a recent systematic review (9) demonstrated that thereis a lack of consistency in the findings of different pharmacogenomicstudies. Once again, this inconsistency is due mainly to thefailure to take into account the various factors that modulatethe genotype–drug response phenotype (1). The same pictureconcerns genetics of essential hypertension. Among thousandsof association studies that have used polymorphisms in candidategenes, few studies demonstrated consistent findings. This maybe due to the variability of the current statistical geneticmethod to define causation in complex polygenic multifactorialdisease such as primary hypertension (10). Most of the geneticand pharmacogenomic studies have major weaknesses related tothree major problems:
Selection criteria: The accuracy and theamount of detailedphenotypic data that can be compared in case-controlstudiesare crucial to the interpretation of the data. For example,in case-control studies, the appropriate control subjects mustbe above the age of onset of "primary" hypertension. Gender,body mass index, ethnic origin, and other biologic variablesmust be taken into account.
Inadequate statistical power ofsmall studies to address complexgenetic questions (11,12):Indeed, in case-control studies,the methods of statisticalgenetics are based on the assumptionthat a genetic variantis involved in hypertension when a higherfrequency of thisvariant is present in hypertensive individuals(12). However,the biologic complexity of polygenic-multifactorialdiseaseschallenges these assumptions. Differences in evolutionaryhistory,population stratification and admixture, epistaticinteraction,context dependency, etc. all may weaken the scientificvalidityof methods that are based on allelic frequency (10).This mayexplain why the case-control studies on candidate genehaveprovided inconsistent findings across populations in polygenic-multifactorialdisease (13,14).
Pharmacogenomics analyses should be usedto differentiate phenotypicheterogeneity, to segment populationsthat seem to be responsiveor unresponsive to a medicine, orto define accurately individualswho might be at higher personalrisk for an adverse event: Toaddress this important point,it is crucial to enroll patientswho have never treated before.For instance, during a chronictreatment with an angiotensin-convertingenzyme inhibitor orangiotensin II antagonist, a great amountof plasma renin, angiotensinogen,angiotensin I, or angiotensinII is available both in the circulationand at the tissue level.After 3 or 4 wk from therapy withdrawal,BP eventually increasesalso because these substances are increasedboth in plasma andin the tissues. This pressor mechanism certainlyis differentfrom what is responsible for the gradual increasein BP withage that underlies the development of "primary" hypertension.Conversely, a long (years) period of treatment with diureticsmay favor the development of an insulin-resistant status that,per se, may increase the risk for organ damage that may appearin the subsequent years (15). Therefore, patients who are alreadyon antihypertensive therapy should be enrolled only for a particulartype of study. Furthermore, when BP is measured as office BP,it should be recorded several times, or, alternatively, 24-hBP monitoring should be used.
Our research group approached the dissection of this complexitythroughout a series of studies on animal models and patientsat different levels of biologic organization: Whole body, organ,cell, subcellular structures, protein, and genes (16). Thesestudies led to the identification of adducin polymorphism asone of the genetic mechanism that, by modulating the constitutivecapacity of tubular cell to reabsorb sodium, may favor the developmentof hypertension with its organ complications.
Adducin is a heterodimeric cytoskeleton protein and consistsof an subunit (103 kD) and either a (97 kD) or a subunit(90 kD). Three human genes (ADD1, ADD2, and ADD3) that map todifferent chromosomes encode these subunits (17). Adducin ishighly conserved through the different species, thus suggestinga role in basic cellular functions. Adducin is a ubiquitouslyexpressed cytoskeleton protein that is involved in the formationof actin-spectrin lattice, actin polymerization, and cell signaltransduction (18,19), including an effect on Na-K ATPase. Figure 1shows ADD1, ADD2, and ADD3 gene structure and SNP identifiedin human and rat hypertension. In humans, two polymorphismsof the ADD1 gene lead to amino acid substitutions: Gly460Trpand S586C (20). Other polymorphisms occur in the human ADD2and ADD3. The first linkage and case-control studies demonstratedan association of the ADD1 Trp allele with hypertension (20).
Figure 1. ADD1, ADD2, ADD3 gene structure and single-nucleotide polymorphism (SNP) identified in human and rat hypertension. Exon-intron structure of ADD genes is indicated by boxes and lines; filled and open boxes represent the exons for coding and noncoding regions of mRNA, respectively. Black filled boxes in ADD2 and ADD3 genes indicate alternative spliced exons in ADD2-4 and ADD3-2 isoforms, respectively. The position of human and rat (underline) SNP is indicated by the arrow. The SNP coordinate is based on the amino acid change (one-letter code, italics) for missense mutation and nucleotide change for silent or intronic mutation. dbSNP ID for human SNP is reported in brackets. The human and rat gene location is reported on the right.
Cell culture and cell-free system experiments helped to elucidatethe molecular mechanisms that make adducin mutation responsiblefor the abnormal cell sodium handling:
In renal cells, transfectionwith the rat-mutated -adducin increasesthe Na-K pump activityand causes a rearrangement of the actincytoskeleton (21).
Ina cell-free system, rat-mutated adducin accelerates actinpolymerization(21), and rat-mutated and human-mutated (ADD1Trp) adducinsbind to and activate the Na-K pump with higheraffinity thanthe respective normal proteins (22).
Studies on the dynamicsof the endocytotic processes in transfectedcells have providedan interpretation for the increased cellularexpression andactivity of the Na-K pump caused by the expressionof the -adducinmutants (23). Cells that are transfected witheither the humanor the rat hypertensive -adducin compared withcells that aretransfected with the wild-type variant show ahigher Na-K pumpactivity and an impaired Na-K pump endocytosisin basal conditions(23) as well as in response to natriureticsignals such as dopamine.Deficient endocytosis of the Na-Kpump therefore might be animportant factor contributing tothe increased renal tubularreabsorption observed in humans(24,25), carrying the mutatedadducin variant. In fact, an efficientendocytosis of the sodiumtransporting proteins is crucial forblunting the rise in systemicarterial pressure when body sodiumincreases.
Impact of Adducin Family Genes on Human Hypertension
In support of these findings are the data collected in humanhypertension: Among hypertensive patients, plasma renin is lowerin carriers of the ADD1 Trp allele than in wild-type homozygotes(20,26). Patients with low renin hypertension have higher BPin the presence of mutated -adducin, and ADD1 Trp/Trp homozygotesexperience the largest increase in BP (26–28). Furthermore,carriers of ADD1 Trp allele, compared with the Gly/Gly homozygotes,show an increased proximal tubular reabsorption measured bylithium clearance (25) and a larger increase of BP after a salineinfusion (24).
In most tissues that are involved in cardiovascular homeostasis(kidney, brain, heart, and vessels), adducin is expressed asa heterodimeric protein that consists of and subunits. Therefore,this protein structure justifies the search for an interactionbetween ADD1 and ADD3. Recently (29), we described an epistaticinteraction between the adducin genes (ADD1 and ADD3) in a largecohort of never-treated hypertensive individuals (n = 512),in which BP was determined with 24-h ambulatory BP monitoring.Patients who carried both the mutated ADD1 Trp allele and ADD3G/G had the higher systolic BP and diastolic BP values (approximately8 mmHg; P = 0.002).
Furthermore, in a study (30) that was conducted in 642 participantswho were randomly recruited from three European populations,peripheral and central pulse pressure (PP), an index of vascularstiffness, was measured. Among carriers of the ADD1 Trp allele,peripheral and central PP were 5.8 and 4.7 mmHg higher in ADD3GG homozygotes than in their AA counterparts, as a result ofan increase in systolic BP. Moreover, in 162 nuclear familiesand 70 unrelated individuals, a test based on the transmissionof ADD3 G allele across families confirmed the interaction betweenthe ADD1 and ADD3 genes. These epistatic interactions, describedin two separate studies, are biochemically consistent with theheterodimeric structure of the cytoskeleton protein adducin.
According to a PubMed literature search, after our initial report(16,26), at least 67 articles addressed the association betweenhuman hypertension and the ADD1 Trp allele. Six human (20,30–34)linkage studies showed positive results when a DNA marker thatmapped to 30 kb from the ADD1 locus or SNP of one of the threeadducin genes was considered either alone or in combinationwith each other or angiotensin-converting enzyme D allele orsalt intake. When DNA markers that mapped at a much larger distancefrom the ADD1 locus were used, negative results were found byfour studies (35–38). Within this large distance, manyhaplotype blocks were included (39). Positive results were alsoobtained in 18 of 20 association studies that, in addition toBP, investigated variables that reflect body sodium or the renin-angiotensinsystem (16,26). Four of five studies (40–44) showed anassociation between -adducin polymorphism and organ damage inhypertensive individuals. There were mixed results from case-controlstudies or studies in predominantly normotensive populationsthat did not consider the above-mentioned variables (see [16,26]for a detailed discussion of this issue).
The association between the ADD1 polymorphism and the responseto diuretics has been evaluated in five studies (20,41,45–47).The rationale for these studies was that in the presence ofconstitutive enhanced tubular sodium reabsorption, drugs suchas diuretics should trigger less counterregulatory mechanisms,thus yielding a more beneficial therapeutic effect. Indeed,three studies (20,45,46) that were designed to test this hypothesisand conducted in never-treated hypertensive patients demonstrateda greater BP response to hydrochlorothiazide (HCTZ) among carriersof the 460Trp allele.
A negative study (47) involved 291 unrelated non-Hispanic blackand 294 unrelated non-Hispanic white adults aged 30 to 59.9yr. The BP value recorded after at least 4 wk from discontinuationof the previous therapy was used as baseline to evaluate theBP response to 25 mg of HCTZ given for 1 mo. Certainly, thisstudy was large enough to conclude that, in that context, norelationship exists between adducin genotypes and the BP responseto the diuretics. However, the important difference with theother similar but positive studies (20,45,46) is that the latterwere performed in newly discovered and never-treated hypertensiveindividuals. After at least 1 mo of run-in and three measurementsof BP on three different occasions, HCTZ was given for 2 mo,and BP was measured after 1 and 2 mo of treatment. In thesepatients, the genotype–BP relationship was not influencedby a previous therapy, different phases of hypertension (becausethey all were in a relatively early hypertensive phase), andthe variety of counterregulatory mechanisms that come into playwith sudden therapy withdrawal. In fact, even after 1 mo fromtherapy withdrawal, the renin response to a standard dose ofdiuretic still is different from that observed in the never-treatedhypertensive status (48).
In accordance with our findings are the results of an observationalstudy (41) on 1038 hypertensive patients who were followed forapproximately 10 yr and treated with a variety of antihypertensivedrugs. These results show that in carriers of the 460Trp ADD1allele (38% of the population), the administration of diureticshalves the incidence of myocardial infarction and stroke whencompared with other antihypertensive treatments that producea similar reduction of BP. The selective beneficial effect ofdiuretics over the other drugs was not present in carriers ofthe Gly/Gly ADD1 genotype. These data support the notion thatmatching of the genetic mechanism with the drug mechanisms ofaction produces a clear benefit probably because the magnitudeof the counterregulatory mechanism and, hence, the global cardiovascularrisk may be minimized. These results bring us to the heart ofthe issue regarding the application of pharmacogenomics to improveour ability to prevent organ damage in hypertension in the subsetof patients who carry a specific genotype or combination ofgenotypes.
The potential of pharmacogenomics to improve treatment of hypertensivepatients is enormous. It will not reduce the size of the populationin whom drugs are effective but may reduce the waste associatedwith empirical optimization of treatment regimens. The addedbenefit of being able to screen out individuals who will experienceunpleasant side effects should improve compliance. The incorporationof SNP haplotype characterization into the development pipelinefor novel drugs would provide an excellent opportunity to determineefficacy haplotypes. Subsequently, this would be used to streamlinetreatment of patients with these novel drugs.
A practical way to "measure" the overall clinical impact ofthe ADD1 Trp allele and then to estimate the size of the populationthat may be affected by this genetic mechanism is to apply avery selective pharmacologic tool that is able to interferewith the sequence of events that are triggered by this allele.Among the available drugs, diuretics are those that better approximatethis tool. The selective beneficial effects of these drugs inreducing BP and preventing myocardial infarction and strokein carriers of the ADD1 Trp allele might be even greater ifdrugs that interfere with adducin but avoid the widely knownside effects of diuretics are developed. However, the majorproblem to overcome in the exploitation of the full potentialof pharmacogenomics is to abandon the "old," "traditional" paradigmsregarding the definition of causation of a given gene variantin a complex multifactorial disease such as hypertension (16,26).Almost all of the reviews concluded that the available dataon genetics or pharmacogenomics of "primary" hypertension areconflicting and do not discuss the implications of the complexityof these diseases that arise from the genetic, environmental,or biologic interactions.
Acknowledgments
This work was supported in part by grants from Ministero Universitàe Ricerca Scientifica of Italy (FIRB grant RBNE01724C_001 toG.B. and PRIN grant 2004069314_01 to G.B.), from Ministero dellaSalute (ICS 110.4/RF02353), and from EURNETGEN, EC funded research(grant QLG1-2000-01137).
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Top
Abstract
Introduction
blockers) reduces the risk for total major cardiovascular events, and larger reductions in BP produce larger reductions in risk. Although the percentage of patients who had hypertension and received treatment increased from 31 to 59% in the period from 1976 to 1980 and to 70% in 2000, the percentage of patients with high BP controlled to <140/90 mmHg is only approximately 25% in Western industrialized countries, and this values has been constant over the past 15 yr. Despite the great number of antihypertensive drugs that are available the poor BP control, adverse effects represent approximately 80% of the causes for the discontinuity of the antihypertensive therapy (8). Pharmacogenomics may reduce the interindividual variation to antihypertensive therapy by tailoring therapy to individual genetic make-up. 
subunit (103 kD) and either a 
subunit (90 kD). Three human genes (ADD1, ADD2, and ADD3) that map to different chromosomes encode these subunits (17). Adducin is highly conserved through the different species, thus suggesting a role in basic cellular functions. Adducin is a ubiquitously expressed cytoskeleton protein that is involved in the formation of actin-spectrin lattice, actin polymerization, and cell signal transduction (18,19), including an effect on Na-K ATPase. Figure 1 shows ADD1, ADD2, and ADD3 gene structure and SNP identified in human and rat hypertension. In humans, two polymorphisms of the ADD1 gene lead to amino acid substitutions: Gly460Trp and S586C (20). Other polymorphisms occur in the human ADD2 and ADD3. The first linkage and case-control studies demonstrated an association of the ADD1 Trp allele with hypertension (20). 
